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Zhang Z, Yang Z, Wang S, Wang X, Mao J. Natural products and ferroptosis: A novel approach for heart failure management. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 142:156783. [PMID: 40286752 DOI: 10.1016/j.phymed.2025.156783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Revised: 03/23/2025] [Accepted: 04/17/2025] [Indexed: 04/29/2025]
Abstract
BACKGROUND The discovery of ferroptosis has brought a revolutionary breakthrough in heart failure treatment, and natural products, as a significant source of drug discovery, are gradually demonstrating their extraordinary potential in regulating ferroptosis and alleviating heart failure symptoms. In addition to chemically synthesized small molecule compounds, natural products have attracted attention as an important source for discovering compounds that target ferroptosis in treating heart failure. PURPOSE Systematically summarize and analyze the research progress on improving heart failure through natural products' modulation of the ferroptosis pathway. METHODS By comprehensively searching authoritative databases like PubMed, Web of Science, and China National Knowledge Infrastructure with keywords such as "heart failure", "cardiovascular disease", "heart disease", "ferroptosis", "natural products", "active compounds", "traditional Chinese medicine formulas", "traditional Chinese medicine", and "acupuncture", we aim to systematically review the mechanism of ferroptosis and its link with heart failure. We also want to explore natural small-molecule compounds, traditional Chinese medicine formulas, and acupuncture therapies that can inhibit ferroptosis to improve heart failure. RESULTS In this review, we not only trace the evolution of the concept of ferroptosis and clearly distinguish it from other forms of cell death but also establish a comprehensive theoretical framework encompassing core mechanisms such as iron overload and system xc-/GSH/GPX4 imbalance, along with multiple auxiliary pathways. On this basis, we innovatively link ferroptosis with various types of heart failure, covering classic heart failure types and extending our research to pre-heart failure conditions such as arrhythmia and aortic aneurysm, providing new insights for early intervention in heart failure. Importantly, this article systematically integrates multiple strategies of natural products for interfering with ferroptosis, ranging from monomeric compounds and bioactive components to crude extracts and further to traditional Chinese medicine formulae. In addition, non-pharmacological means such as acupuncture are also included. CONCLUSION This study fills the gap in the systematic description of the relationship between ferroptosis and heart failure and the therapeutic strategies of natural products, aiming to provide patients with more diverse treatment options and promote the development of the heart failure treatment field.
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Affiliation(s)
- Zeyu Zhang
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, No.88 Changling Road, Xiqing District, Tianjin 300381, PR China; Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China
| | - Zhihua Yang
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, No.88 Changling Road, Xiqing District, Tianjin 300381, PR China; Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China
| | - Shuai Wang
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, No.88 Changling Road, Xiqing District, Tianjin 300381, PR China
| | - Xianliang Wang
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, No.88 Changling Road, Xiqing District, Tianjin 300381, PR China.
| | - Jingyuan Mao
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, No.88 Changling Road, Xiqing District, Tianjin 300381, PR China.
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Mustafa AM, El-Shiekh RA, Esmail MM, Hassan E, Senna MM, Ebid N, Elgindy AM. Surveying the Therapeutic Potentials of Isoliquiritigenin (ISL): A Comprehensive Review. Chem Biodivers 2025:e202500456. [PMID: 40274535 DOI: 10.1002/cbdv.202500456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Revised: 04/22/2025] [Accepted: 04/23/2025] [Indexed: 04/26/2025]
Abstract
Isoliquiritigenin (ISL), a major chalcone-type flavonoid produced predominantly from liquorice roots (Glycyrrhiza species), has exceptional therapeutic potential across a wide range of pharmacological activities. ISL has numerous benefits including antioxidant, anti-inflammatory, antidiabetic, cardioprotective, hepatoprotective, neuroprotective, and anticancer activities. This review gathers the pharmacological effects of ISL remarking into its mechanism of actions such as how it modulates oxidative stress, inflammatory pathways, glucose metabolism, and cancer growth, demonstrating its pharmacological versatility. The review emphasizes new advances in the field, allowing for more rational development and clinical use of ISL in medicine. However, further research is required to confirm the target-organ toxicity or side-effect investigations.
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Affiliation(s)
- Aya M Mustafa
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Egyptian Russian University, Cairo, Egypt
| | - Riham A El-Shiekh
- Department of Pharmacognosy, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Manar M Esmail
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Egyptian Russian University, Cairo, Egypt
| | - Eslam Hassan
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Egyptian Russian University, Cairo, Egypt
| | - Mohamed Magdy Senna
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Egyptian Russian University, Cairo, Egypt
| | - Nouran Ebid
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Egyptian Russian University, Cairo, Egypt
| | - Ali M Elgindy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Egyptian Russian University, Cairo, Egypt
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Zhong L, Hou X, Tian Y, Fu X. Exercise and dietary interventions in the management of diabetic cardiomyopathy: mechanisms and implications. Cardiovasc Diabetol 2025; 24:159. [PMID: 40205621 PMCID: PMC11983742 DOI: 10.1186/s12933-025-02702-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Accepted: 03/22/2025] [Indexed: 04/11/2025] Open
Abstract
The global prevalence of diabetes is rapidly increasing, significantly raising the risk of various cardiovascular diseases. Among these, diabetic cardiomyopathy (DCM) is a distinct and critical complication characterized by ventricular hypertrophy and impaired myocardial contractility, ultimately progressing to heart failure and making it a leading cause of mortality among diabetic patients. Despite advances in pharmacological therapies, the effectiveness of managing cardiac dysfunction in DCM remains challenging. Consequently, exploring additional therapeutic strategies for the prevention and treatment of DCM is urgently needed. Beyond pharmacological approaches, lifestyle modifications, particularly exercise and dietary interventions, play a fundamental role in managing DCM due to their significant cardiovascular benefits in diabetic patients. This review synthesizes recent advancements in the field, elucidating the underlying mechanisms through which exercise and dietary interventions influence DCM pathophysiology. By integrating these strategies, we aim to facilitate the development of personalized exercise and dietary regimens that effectively mitigate or prevent DCM progression.
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Affiliation(s)
- Ling Zhong
- Department of Endocrinology and Metabolism, Department of Biotherapy, Laboratory of Diabetes and Metabolism Research, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Xiaojie Hou
- Department of Cardiovascular Surgery, Cardiovascular Surgery Research Laboratory, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Yan Tian
- Department of Endocrinology and Metabolism, Department of Biotherapy, Laboratory of Diabetes and Metabolism Research, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
| | - Xianghui Fu
- Department of Endocrinology and Metabolism, Department of Biotherapy, Laboratory of Diabetes and Metabolism Research, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
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Singh H, Singh R, Singh A, Singh H, Singh G, Kaur S, Singh B. Role of oxidative stress in diabetes-induced complications and their management with antioxidants. Arch Physiol Biochem 2024; 130:616-641. [PMID: 37571852 DOI: 10.1080/13813455.2023.2243651] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 05/30/2023] [Accepted: 06/02/2023] [Indexed: 08/13/2023]
Abstract
Diabetes mellitus (DM) is a huge global health issue and one of the most studied diseases, with a large global prevalence. Oxidative stress is a cytotoxic consequence of the excessive development of ROS and suppression of the antioxidant defense system for ROS elimination, which accelerates the progression of diabetes complications such as diabetic neuropathy, retinopathy, and nephropathy. Hyperglycaemia induced oxidative stress causes the activation of seven major pathways implicated in the pathogenesis of diabetic complications. These pathways increase the production of ROS and RNS, which contributes to dysregulated autophagy, gene expression changes, and the development of numerous pro-inflammatory mediators which may eventually lead to diabetic complications. This review will illustrate that oxidative stress plays a vital role in the pathogenesis of diabetic complications, and the use of antioxidants will help to reduce oxidative stress and thus may alleviate diabetic complications.
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Affiliation(s)
- Hasandeep Singh
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, 143005, India
| | - Rajanpreet Singh
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, 143005, India
| | - Arshdeep Singh
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, 143005, India
| | - Harshbir Singh
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, 143005, India
| | - Gurpreet Singh
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, 143005, India
| | - Sarabjit Kaur
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, 143005, India
| | - Balbir Singh
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, 143005, India
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Durumutla HB, Prabakaran AD, El Abdellaoui Soussi F, Akinborewa O, Latimer H, McFarland K, Piczer K, Werbrich C, Jain MK, Haldar SM, Quattrocelli M. Glucocorticoid chronopharmacology promotes glucose metabolism in heart through a cardiomyocyte-autonomous transactivation program. JCI Insight 2024; 9:e182599. [PMID: 39378111 PMCID: PMC11601906 DOI: 10.1172/jci.insight.182599] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Accepted: 10/04/2024] [Indexed: 10/10/2024] Open
Abstract
Circadian time of intake gates the cardioprotective effects of glucocorticoid administration in both healthy and infarcted hearts. The cardiomyocyte-specific glucocorticoid receptor (GR) and its cofactor, Krüppel-like factor 15 (KLF15), play critical roles in maintaining normal heart function in the long term and serve as pleiotropic regulators of cardiac metabolism. Despite this understanding, the cardiomyocyte-autonomous metabolic targets influenced by the concerted epigenetic action of the GR/KLF15 axis remain undefined. Here, we demonstrated the critical roles of the cardiomyocyte-specific GR and KLF15 in orchestrating a circadian-dependent glucose oxidation program within the heart. Combining integrated transcriptomics and epigenomics with cardiomyocyte-specific inducible ablation of GR or KLF15, we identified their synergistic role in the activation of adiponectin receptor expression (Adipor1) and the mitochondrial pyruvate complex (Mpc1/2), thereby enhancing insulin-stimulated glucose uptake and pyruvate oxidation. Furthermore, in obese diabetic (db/db) mice exhibiting insulin resistance and impaired glucose oxidation, light-phase prednisone administration, as opposed to dark-phase prednisone dosing, restored cardiomyocyte glucose oxidation and improved diastolic function. These effects were blocked by combined in vivo knockdown of GR and KLF15 levels in db/db hearts. In summary, this study leveraged the circadian-dependent cardioprotective effects of glucocorticoids to identify cardiomyocyte-autonomous targets for the GR/KLF15 axis in glucose metabolism.
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Affiliation(s)
- Hima Bindu Durumutla
- Molecular Cardiovascular Biology, Heart Institute, Cincinnati Children’s Hospital Medical Center and Department of Pediatrics, and
| | - Ashok Daniel Prabakaran
- Molecular Cardiovascular Biology, Heart Institute, Cincinnati Children’s Hospital Medical Center and Department of Pediatrics, and
| | - Fadoua El Abdellaoui Soussi
- Molecular Cardiovascular Biology, Heart Institute, Cincinnati Children’s Hospital Medical Center and Department of Pediatrics, and
| | - Olukunle Akinborewa
- Molecular Cardiovascular Biology, Heart Institute, Cincinnati Children’s Hospital Medical Center and Department of Pediatrics, and
- Department of Pharmacology, Physiology and Neurobiology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Hannah Latimer
- Molecular Cardiovascular Biology, Heart Institute, Cincinnati Children’s Hospital Medical Center and Department of Pediatrics, and
| | - Kevin McFarland
- Molecular Cardiovascular Biology, Heart Institute, Cincinnati Children’s Hospital Medical Center and Department of Pediatrics, and
| | - Kevin Piczer
- Molecular Cardiovascular Biology, Heart Institute, Cincinnati Children’s Hospital Medical Center and Department of Pediatrics, and
| | - Cole Werbrich
- Molecular Cardiovascular Biology, Heart Institute, Cincinnati Children’s Hospital Medical Center and Department of Pediatrics, and
| | - Mukesh K. Jain
- Department of Cell Biology and Biochemistry, Brown University, Providence, Rhode Island, USA
| | - Saptarsi M. Haldar
- Amgen Research, South San Francisco, California, USA
- Gladstone Institutes, San Francisco, California, USA
- Department of Medicine, Cardiology Division, UCSF, San Francisco, California, USA
| | - Mattia Quattrocelli
- Molecular Cardiovascular Biology, Heart Institute, Cincinnati Children’s Hospital Medical Center and Department of Pediatrics, and
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Xia J, Li X, Bai C, Han X. Research Progress of Coenzyme Q in Diabetes Mellitus and Its Common Complications. Diabetes Metab Syndr Obes 2024; 17:3629-3641. [PMID: 39376660 PMCID: PMC11457790 DOI: 10.2147/dmso.s481690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Accepted: 09/16/2024] [Indexed: 10/09/2024] Open
Abstract
Coenzyme Q has garnered significant attention due to its potential role in enhancing cellular energy production and its antioxidant properties. We delve into the therapeutic potential of coenzyme Q in managing diabetes mellitus and its complications, highlighting its capacity to improve mitochondrial function, reduce inflammation and oxidative stress, and correct lipid profiles. Coenzyme Q has shown promise in ameliorating insulin resistance and alleviating complications such as diabetic peripheral neuropathy, kidney disease, retinopathy, and cardiomyopathy. However, its clinical application is limited by poor bio-availability. This review also provides a comprehensive overview of current therapeutic strategies for diabetes complications involving coenzyme Q, including stimulating endogenous synthesis and utilizing carrier transport systems, offering insights into mechanisms for enhancing coenzyme Q bio-availability. These findings suggest that, with improved delivery methods, coenzyme Q could become a valuable adjunct therapy in the management of diabetes mellitus.
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Affiliation(s)
- Jingdong Xia
- Affiliated Hospital of Chifeng University, Chifeng, The Inner Mongol Autonomous Region, Chifeng, People’s Republic of China
- Key Laboratory of Research on Human Genetic Diseases at Universities of Inner Mongolia Autonomous Region, Chifeng, People’s Republic of China
| | - Xiudan Li
- Affiliated Hospital of Chifeng University, Chifeng, The Inner Mongol Autonomous Region, Chifeng, People’s Republic of China
- Key Laboratory of Research on Human Genetic Diseases at Universities of Inner Mongolia Autonomous Region, Chifeng, People’s Republic of China
| | - Chunying Bai
- Key Laboratory of Research on Human Genetic Diseases at Universities of Inner Mongolia Autonomous Region, Chifeng, People’s Republic of China
| | - Xuchen Han
- Affiliated Hospital of Chifeng University, Chifeng, The Inner Mongol Autonomous Region, Chifeng, People’s Republic of China
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Liza, Hussain G, Malik A, Akhtar S, Anwar H. Artemisia vulgaris Extract as a Novel Therapeutic Approach for Reversing Diabetic Cardiomyopathy in a Rat Model. Pharmaceuticals (Basel) 2024; 17:1046. [PMID: 39204151 PMCID: PMC11358959 DOI: 10.3390/ph17081046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 07/12/2024] [Accepted: 07/17/2024] [Indexed: 09/03/2024] Open
Abstract
Diabetic cardiomyopathy, a severe diabetic complication, impairs heart function, leading to heart failure. Treatment that effectively addresses this condition without causing side effects is urgently needed. Current anti-hyperglycemic therapies are expensive, has side effects and do not effectively prevent cardiac remodeling. Therefore, it is important to explore natural products that may have the potential to reverse cardiac remodeling. That is why the aim of the current study was to determine the left ventricular remodeling potential of the methanolic extract of Artemisia vulgaris in a diabetic cardiomyopathy rat model. Following the initial comprehensive phytochemical evaluation of plant phenolic and flavonoid content, which showed strong anti-hyperglycemic and antioxidant activities, an extract of Artemisia vulgaris was administered in an in vivo experiment. Diabetic cardiomyopathy was induced in Wistar albino rats according to previously described protocols in the literature, and the effect of treatment was checked by serum and histopathological analysis after 45 days. Artemisia vulgaris treatment significantly (p ≤ 0.05) reduced fasting blood glucose (108.5 ± 1.75 mg/dL), glycated hemoglobin (4.03 ± 0.12 %), serum glucose (116.66 ± 3.28 mg/dL), insulin (15.66 ± 0.66 ng/mL), total oxidant status (54.66 ± 3.22 µmol H2O2Equiv.L-1), Malondialdehyde (0.20 ± 0.01 mmol/L), total cholesterol (91.16 ± 3.35 mg/dL), triglycerides (130.66 ± 3.15 mg/dL), low-density lipids (36.57 ± 1.02 mg/dL), sodium (140 ± 3.21 mmol/L), calcium (10.44 ± 0.24 mmol/L), creatine kinase MB (1227.5 ± 17.89 IU/L), lactate dehydrogenase (1300 ± 34.64 IU/L), C-reactive protein (30 ± 0.57 pg/mL), tumor necrosis factor-α (58.66 ± 1.76 pg/mL), atrial natriuretic peptide (2.53 ± 0.04 pg/mL), B-type natriuretic peptide (10.66 ± 0.44 pg/mL), aspartate aminotransferase (86.5 ± 4.99 U/L), Alanine Transaminase (55.33 ± 2.90 U/L), urea (25.33 ± 1.15 mg/dL) and creatinine (0.64 ± 0.02 mg/dL) but significantly increased (p ≤ 0.05) total antioxidant capacity (1.73 ± 0.07 mmol Trolox Equil./L), high-density lipids (40 ± 1.59 mg/dL) and potassium (3.82 ± 0.04 mmol/L) levels. ECG and histopathology confirmed the significant improvement in remodeling and the reversal of structural changes in the heart and pancreas. In conclusion, Artemisia vulgaris possesses significant left ventricular remodeling potential in course of diabetes-induced cardiomyopathy.
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Affiliation(s)
- Liza
- Department of Physiology, Faculty of Life Sciences, Government College University, Faisalabad 38000, Pakistan; (L.); (G.H.)
| | - Ghulam Hussain
- Department of Physiology, Faculty of Life Sciences, Government College University, Faisalabad 38000, Pakistan; (L.); (G.H.)
| | - Abdul Malik
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11564, Saudi Arabia;
| | - Suhail Akhtar
- Department of Biochemistry, A.T. Still University of Health Sciences, Kirksville, MO 63501, USA;
| | - Haseeb Anwar
- Department of Physiology, Faculty of Life Sciences, Government College University, Faisalabad 38000, Pakistan; (L.); (G.H.)
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Zhang Z, Yang Z, Wang S, Wang X, Mao J. Decoding ferroptosis: Revealing the hidden assassin behind cardiovascular diseases. Biomed Pharmacother 2024; 176:116761. [PMID: 38788596 DOI: 10.1016/j.biopha.2024.116761] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 05/09/2024] [Accepted: 05/17/2024] [Indexed: 05/26/2024] Open
Abstract
The discovery of regulatory cell death processes has driven innovation in cardiovascular disease (CVD) therapeutic strategies. Over the past decade, ferroptosis, an iron-dependent form of regulated cell death driven by excessive lipid peroxidation, has been shown to drive the development of multiple CVDs. This review provides insights into the evolution of the concept of ferroptosis, the similarities and differences with traditional modes of programmed cell death (e.g., apoptosis, autophagy, and necrosis), as well as the core regulatory mechanisms of ferroptosis (including cystine/glutamate transporter blockade, imbalance of iron metabolism, and lipid peroxidation). In addition, it provides not only a detailed review of the role of ferroptosis and its therapeutic potential in widely studied CVDs such as coronary atherosclerotic heart disease, myocardial infarction, myocardial ischemia/reperfusion injury, heart failure, cardiomyopathy, and aortic aneurysm but also an overview of the phenomenon and therapeutic perspectives of ferroptosis in lesser-addressed CVDs such as cardiac valvulopathy, pulmonary hypertension, and sickle cell disease. This article aims to integrate this knowledge to provide a comprehensive view of ferroptosis in a wide range of CVDs and to drive innovation and progress in therapeutic strategies in this field.
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Affiliation(s)
- Zeyu Zhang
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China; Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Zhihua Yang
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China; Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Shuai Wang
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China
| | - Xianliang Wang
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China.
| | - Jingyuan Mao
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China.
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Oksen D, Aslan M. Impact of oxidative stress on myocardial performance in patients with diabetes: a focus on subclinical left ventricular dysfunction. BMJ Open Diabetes Res Care 2024; 12:e004153. [PMID: 38886070 PMCID: PMC11184181 DOI: 10.1136/bmjdrc-2024-004153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Accepted: 06/02/2024] [Indexed: 06/20/2024] Open
Abstract
INTRODUCTION Oxidative stress is known to affect left ventricular functions negatively. There is a strong bidirectional connection between diabetes mellitus (DM) and oxidative stress. In parallel, left ventricular dysfunction is observed more frequently, even in patients with DM without other risk factors. In this context, the objective of this study is to comparatively investigate the potential relationship between oxidative stress and subclinical left ventricular dysfunction (SCLVD) assessed by Myocardial Performance Index (MPI) in patients with and without DM. RESEARCH DESIGN AND METHODS The sample of this observational cross-sectional single-center study consisted of 151 patients who were evaluated for oxidative stress and SCLVD by tissue Doppler echocardiography. Patients' total oxidant status (TOS), total antioxidant status (TAS), and Oxidative Stress Index (OSI) values were calculated. The effects of oxidative stress and DM on MPI were analyzed. RESULTS There were 81 patients with DM (mean age: 46.17±10.33 years) and 70 healthy individuals (mean age: 45.72±9.04 years). Mean TOS and OSI values of the DM group were higher than healthy individuals (5.72±0.55 vs 5.31±0.50, p = <0.001; and 4.92±1.93 vs 1.79±0.39, p = <0.001; respectively). The mean TAS value of the DM group was significantly lower than the healthy group (1.21±0.40 vs 3.23±0.51, p = <0.001). There was a significant correlation between OSI and MPI mitral in the DM group (R 0.554, p = <0.001) but not in the healthy group (R -0.069, p=0.249). CONCLUSIONS Both oxidative stress and myocardial dysfunction were found to be more common in patients with DM. The study's findings indicated the negative effect of oxidative stress on myocardial functions. Accordingly, increased oxidative stress caused more significant deterioration in MPI in patients with DM compared with healthy individuals.
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Affiliation(s)
- Dogac Oksen
- Cardiology Department, Altinbas Universitesi, Istanbul, Turkey
| | - Muzaffer Aslan
- Cardiology Department, Siirt University, Siirt, Siirt, Turkey
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Luo J, Hu S, Liu J, Shi L, Luo L, Li W, Cai Y, Tang J, Liu S, Fu M, Dong R, Yang Y, Tu L, Xu X. Cardiac-specific PFKFB3 overexpression prevents diabetic cardiomyopathy via enhancing OPA1 stabilization mediated by K6-linked ubiquitination. Cell Mol Life Sci 2024; 81:228. [PMID: 38777955 PMCID: PMC11111656 DOI: 10.1007/s00018-024-05257-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Revised: 04/01/2024] [Accepted: 04/27/2024] [Indexed: 05/25/2024]
Abstract
Diabetic cardiomyopathy (DCM) is a prevalent complication of type 2 diabetes (T2D). 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) is a glycolysis regulator. However, the potential effects of PFKFB3 in the DCM remain unclear. In comparison to db/m mice, PFKFB3 levels decreased in the hearts of db/db mice. Cardiac-specific PFKFB3 overexpression inhibited myocardial oxidative stress and cardiomyocyte apoptosis, suppressed mitochondrial fragmentation, and partly restored mitochondrial function in db/db mice. Moreover, PFKFB3 overexpression stimulated glycolysis. Interestingly, based on the inhibition of glycolysis, PFKFB3 overexpression still suppressed oxidative stress and apoptosis of cardiomyocytes in vitro, which indicated that PFKFB3 overexpression could alleviate DCM independent of glycolysis. Using mass spectrometry combined with co-immunoprecipitation, we identified optic atrophy 1 (OPA1) interacting with PFKFB3. In db/db mice, the knockdown of OPA1 receded the effects of PFKFB3 overexpression in alleviating cardiac remodeling and dysfunction. Mechanistically, PFKFB3 stabilized OPA1 expression by promoting E3 ligase NEDD4L-mediated atypical K6-linked polyubiquitination and thus prevented the degradation of OPA1 by the proteasomal pathway. Our study indicates that PFKFB3/OPA1 could be potential therapeutic targets for DCM.
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Affiliation(s)
- Jinlan Luo
- Department of Geriatric Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- Division of Cardiology and Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Shuiqing Hu
- Division of Cardiology and Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Jingrui Liu
- Division of Cardiology and Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Lili Shi
- Department of Geriatric Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Liman Luo
- Department of Geriatric Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Wenhua Li
- Department of Geriatric Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yueting Cai
- Division of Cardiology and Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Jiaxin Tang
- Department of Geriatric Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Siyang Liu
- Department of Geriatric Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Menglu Fu
- Department of Geriatric Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Ruolan Dong
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yan Yang
- Health Management Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Ling Tu
- Department of Geriatric Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, 430030, China.
| | - Xizhen Xu
- Division of Cardiology and Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, 430030, China.
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11
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Graczyk P, Dach A, Dyrka K, Pawlik A. Pathophysiology and Advances in the Therapy of Cardiomyopathy in Patients with Diabetes Mellitus. Int J Mol Sci 2024; 25:5027. [PMID: 38732253 PMCID: PMC11084712 DOI: 10.3390/ijms25095027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 04/19/2024] [Accepted: 05/01/2024] [Indexed: 05/13/2024] Open
Abstract
Diabetes mellitus (DM) is known as the first non-communicable global epidemic. It is estimated that 537 million people have DM, but the condition has been properly diagnosed in less than half of these patients. Despite numerous preventive measures, the number of DM cases is steadily increasing. The state of chronic hyperglycaemia in the body leads to numerous complications, including diabetic cardiomyopathy (DCM). A number of pathophysiological mechanisms are behind the development and progression of cardiomyopathy, including increased oxidative stress, chronic inflammation, increased synthesis of advanced glycation products and overexpression of the biosynthetic pathway of certain compounds, such as hexosamine. There is extensive research on the treatment of DCM, and there are a number of therapies that can stop the development of this complication. Among the compounds used to treat DCM are antiglycaemic drugs, hypoglycaemic drugs and drugs used to treat myocardial failure. An important element in combating DCM that should be kept in mind is a healthy lifestyle-a well-balanced diet and physical activity. There is also a group of compounds-including coenzyme Q10, antioxidants and modulators of signalling pathways and inflammatory processes, among others-that are being researched continuously, and their introduction into routine therapies is likely to result in greater control and more effective treatment of DM in the future. This paper summarises the latest recommendations for lifestyle and pharmacological treatment of cardiomyopathy in patients with DM.
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Affiliation(s)
- Patryk Graczyk
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (P.G.); (A.D.)
| | - Aleksandra Dach
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (P.G.); (A.D.)
| | - Kamil Dyrka
- Department of Pediatric Endocrinology and Rheumatology, Institute of Pediatrics, Poznan University of Medical Sciences, 60-572 Poznan, Poland;
| | - Andrzej Pawlik
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (P.G.); (A.D.)
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12
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Samimi F, Namiranian N, Sharifi-Rigi A, Siri M, Abazari O, Dastghaib S. Coenzyme Q10: A Key Antioxidant in the Management of Diabetes-Induced Cardiovascular Complications-An Overview of Mechanisms and Clinical Evidence. Int J Endocrinol 2024; 2024:2247748. [PMID: 38524871 PMCID: PMC10959587 DOI: 10.1155/2024/2247748] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 03/06/2024] [Accepted: 03/07/2024] [Indexed: 03/26/2024] Open
Abstract
Background Diabetes mellitus (DM) presents a significant global health challenge with considerable cardiovascular implications. Coenzyme Q10 (CoQ10) has gained recognition for its potential as a natural antioxidant supplement in the management of diabetes and its associated cardiovascular complications. Aim This comprehensive review systematically examines the scientific rationale underlying the therapeutic properties of CoQ10 in mitigating the impact of diabetes and its cardiovascular consequences. The analysis encompasses preclinical trials (in vitro and in vivo) and clinical studies evaluating the efficacy and mechanisms of action of CoQ10. Result & Discussion. Findings reveal that CoQ10, through its potent antioxidant and anti-inflammatory attributes, demonstrates significant potential in reducing oxidative stress, ameliorating lipid profiles, and regulating blood pressure, which are crucial aspects in managing diabetes-induced cardiovascular complications. CoQ10, chemically represented as C59H90O4, was administered in capsule form for human studies at doses of 50, 100, 150, 200, and 300 mg per day and at concentrations of 10 and 20 μM in sterile powder for experimental investigations and 10 mg/kg in powder for mouse studies, according to the published research. Clinical trials corroborate these preclinical findings, demonstrating improved glycemic control, lipid profiles, and blood pressure in patients supplemented with CoQ10. Conclusion In conclusion, CoQ10 emerges as a promising natural therapeutic intervention for the comprehensive management of diabetes and its associated cardiovascular complications. Its multifaceted impacts on the Nrf2/Keap1/ARE pathway, oxidative stress, and metabolic regulation highlight its potential as an adjunct in the treatment of diabetes and related cardiovascular disorders. However, further extensive clinical investigations are necessary to fully establish its therapeutic potential and assess potential synergistic effects with other compounds.
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Affiliation(s)
- Fatemeh Samimi
- Diabetes Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
- Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Nasim Namiranian
- Diabetes Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Ali Sharifi-Rigi
- Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Morvarid Siri
- Autophagy Research Center, Department of Clinical Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Omid Abazari
- Department of Clinical Biochemistry, School of Medicine, Shahid Sadoughi University of Medical Sciences and Health Services, Yazd, Iran
| | - Sanaz Dastghaib
- Endocrinology and Metabolism Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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13
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Khaledi K, Hoseini R, Gharzi A. The impact of vitamin D on type 2 diabetes management: boosting PTP1B gene expression and physical activity benefits in rats. GENES & NUTRITION 2024; 19:4. [PMID: 38431555 PMCID: PMC10908205 DOI: 10.1186/s12263-023-00736-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Accepted: 11/15/2023] [Indexed: 03/05/2024]
Abstract
BACKGROUND The protein tyrosine phosphatase 1B (PTP1B) plays a crucial role in the development of insulin resistance. Aerobic training (AT) and vitamin D (Vit D) supplementation have been shown to individually improve glucose tolerance and diabetes-related factors. However, the impact of their combined effect on PTP1B gene expression and serum irisin in the visceral adipose tissue remains unknown. This study aims to investigate whether 8 weeks of combined AT with Vit D supplementation can improve the expression of PTP1B in adipose tissue and serum irisin in obese rats with type 2 diabetes (T2D). METHODS Fifty male Wistar rats were divided into two groups: diabetic (n = 40) and non-diabetic (ND; n = 10). The diabetic rats were further divided into four groups: aerobic training with vitamin D supplementation (D + AT + Vit D; n = 10), aerobic training only (D + AT; n = 10), vitamin D supplementation only (D + Vit D; n = 10), and control (D + C; n = 10). The D + Vit D and D + AT + Vit D groups received 5000 IU of vitamin D via injection once a week, while the D + AT and D + C groups received sesame oil. Diabetes was induced in all groups except the nondiabetic group by intraperitoneal (IP) injection of streptozotocin. At the end of the intervention, blood and adipose tissue samples were collected, and RNA was extracted from adipose tissue for real-time PCR analysis of PPTP1B gene expression. RESULTS There was an increase in serum Vit D and irisin levels and a decrease in HOMA-IR and PTP1B gene expression in the diabetic rat model treated with D + AT and injected with 50,000 IU/kg/week of Vit D. Comparatively, when treated with D + AT + Vit D, the downregulation of PTP1B was significantly higher (p = 0.049; p = 0.004), and there was a significant increase in irisin (p = 0.010; p = 0.001). CONCLUSION The present study shows that the combined AT and Vit D supplementation positively impacts the expression of PTP1B in adipose tissue and serum irisin in rats with T2D. These findings suggest that combining AT with Vit D supplementation can provide a new and effective strategy to improve glucose tolerance and diabetes-related factors in individuals with T2D by regulating the expression of PTP1B in adipose tissue and promoting the synthesis of beneficial irisin protein.
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Affiliation(s)
- Kimya Khaledi
- Department of Exercise Physiology, Faculty of Sport Sciences, Razi University, Kermanshah, Iran
| | - Rastegar Hoseini
- Department of Exercise Physiology, Faculty of Sport Sciences, Razi University, Kermanshah, Iran.
| | - Ahmad Gharzi
- Department of Biology, Faculty of Science, Razi University, Kermanshah, Iran
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14
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Shakour N, Karami S, Iranshahi M, Butler AE, Sahebkar A. Antifibrotic effects of sodium-glucose cotransporter-2 inhibitors: A comprehensive review. Diabetes Metab Syndr 2024; 18:102934. [PMID: 38154403 DOI: 10.1016/j.dsx.2023.102934] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 11/25/2023] [Accepted: 12/20/2023] [Indexed: 12/30/2023]
Abstract
BACKGROUND AND AIMS Scar tissue accumulation in organs is the underlying cause of many fibrotic diseases. Due to the extensive array of organs affected, the long-term nature of fibrotic processes and the large number of people who suffer from the negative impact of these diseases, they constitute a serious health problem for modern medicine and a huge economic burden on society. Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are a relatively new class of anti-diabetic pharmaceuticals that offer additional benefits over and above their glucose-lowering properties; these medications modulate a variety of diseases, including fibrosis. Herein, we have collated and analyzed all available research on SGLT2is and their effects on organ fibrosis, together with providing a proposed explanation as to the underlying mechanisms. METHODS PubMed, ScienceDirect, Google Scholar and Scopus were searched spanning the period from 2012 until April 2023 to find relevant articles describing the antifibrotic effects of SGLT2is. RESULTS The majority of reports have shown that SGLT2is are protective against lung, liver, heart and kidney fibrosis as well as arterial stiffness. According to the results of clinical trials and animal studies, many SGLT2 inhibitors are promising candidates for the treatment of fibrosis. Recent studies have demonstrated that SGLT2is affect an array of cellular processes, including hypoxia, inflammation, oxidative stress, the renin-angiotensin system and metabolic activities, all of which have been linked to fibrosis. CONCLUSION Extensive evidence indicates that SGLT2is are promising treatments for fibrosis, demonstrating protective effects in various organs and influencing key cellular processes linked to fibrosis.
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Affiliation(s)
- Neda Shakour
- Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran; Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Shima Karami
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mehrdad Iranshahi
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Alexandra E Butler
- Research Department, Royal College of Surgeons in Ireland, Adliya, Bahrain
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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15
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Huang Z, Ma Y, Sun Z, Cheng L, Wang G. Ferroptosis: potential targets and emerging roles in pancreatic diseases. Arch Toxicol 2024; 98:75-94. [PMID: 37934210 DOI: 10.1007/s00204-023-03625-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Accepted: 10/11/2023] [Indexed: 11/08/2023]
Abstract
Ferroptosis is a newly discovered form of regulatory cell death characterized by excessive iron-dependent lipid peroxidation. In the past decade, significant breakthroughs have been made in comprehending the features and regulatory mechanisms of ferroptosis, and it has been confirmed that ferroptosis plays a pivotal role in the pathophysiological processes of various diseases, including tumors, inflammation, neurodegenerative diseases, and infectious diseases. The pancreas, which is the second largest digestive gland in the human body and has both endocrine and exocrine functions, is a vital organ for controlling digestion and metabolism. In recent years, numerous studies have confirmed that ferroptosis is closely related to pancreatic diseases, which is attributed to abnormal iron accumulation, as an essential biochemical feature of ferroptosis, is often present in the pathological processes of various pancreatic exocrine and endocrine diseases and the vulnerability of the pancreas to oxidative stress stimulation and damage. Therefore, comprehending the regulatory mechanism of ferroptosis in pancreatic diseases may provide valuable new insights into treatment strategies. In this review, we first summarize the hallmark features of ferroptosis and then analyze the exact mechanisms by which ferroptosis is precisely regulated at multiple levels and links, including iron metabolism, lipid metabolism, the GPX4-mediated ferroptosis defense system, the GPX4-independent ferroptosis defense system, and the regulation of autophagy on ferroptosis. Finally, we discuss the role of ferroptosis in the occurrence and development of pancreatic diseases and summarize the feasibility and limitations of ferroptosis as a therapeutic target for pancreatic diseases.
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Affiliation(s)
- Zijian Huang
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang, China
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang, China
| | - Yuan Ma
- Medical Department, The First Affifiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang, China
| | - Zhiguo Sun
- Department of General Surgery, The Affiliated Hongqi Hospital of Mudanjiang Medical University, Mudanjiang, 157011, Heilongjiang, China
| | - Long Cheng
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang, China
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang, China
| | - Gang Wang
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang, China.
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16
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Trotta MC, Herman H, Ciceu A, Mladin B, Rosu M, Lepre CC, Russo M, Bácskay I, Fenyvesi F, Marfella R, Hermenean A, Balta C, D’Amico M. Chrysin-based supramolecular cyclodextrin-calixarene drug delivery system: a novel approach for attenuating cardiac fibrosis in chronic diabetes. Front Pharmacol 2023; 14:1332212. [PMID: 38169923 PMCID: PMC10759242 DOI: 10.3389/fphar.2023.1332212] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Accepted: 12/04/2023] [Indexed: 01/05/2024] Open
Abstract
Introduction: Cardiac fibrosis is strongly induced by diabetic conditions. Both chrysin (CHR) and calixarene OTX008, a specific inhibitor of galectin 1 (Gal-1), seem able to reduce transforming growth factor beta (TGF-β)/SMAD pro-fibrotic pathways, but their use is limited to their low solubility. Therefore, we formulated a dual-action supramolecular system, combining CHR with sulfobutylated β-cyclodextrin (SBECD) and OTX008 (SBECD + OTX + CHR). Here we aimed to test the anti-fibrotic effects of SBECD + OTX + CHR in hyperglycemic H9c2 cardiomyocytes and in a mouse model of chronic diabetes. Methods: H9c2 cardiomyocytes were exposed to normal (NG, 5.5 mM) or high glucose (HG, 33 mM) for 48 h, then treated with SBECD + OTX + CHR (containing OTX008 0.75-1.25-2.5 µM) or the single compounds for 6 days. TGF-β/SMAD pathways, Mitogen-Activated Protein Kinases (MAPKs) and Gal-1 levels were assayed by Enzyme-Linked Immunosorbent Assays (ELISAs) or Real-Time Quantitative Reverse Transcription Polymerase chain reaction (qRT-PCR). Adult CD1 male mice received a single intraperitoneal (i.p.) administration of streptozotocin (STZ) at a dosage of 102 mg/kg body weight. From the second week of diabetes, mice received 2 times/week the following i.p. treatments: OTX (5 mg/kg)-SBECD; OTX (5 mg/kg)-SBECD-CHR, SBECD-CHR, SBECD. After a 22-week period of diabetes, mice were euthanized and cardiac tissue used for tissue staining, ELISA, qRT-PCR aimed to analyse TGF-β/SMAD, extracellular matrix (ECM) components and Gal-1. Results: In H9c2 cells exposed to HG, SBECD + OTX + CHR significantly ameliorated the damaged morphology and reduced TGF-β1, its receptors (TGFβR1 and TGFβR2), SMAD2/4, MAPKs and Gal-1. Accordingly, these markers were reduced also in cardiac tissue from chronic diabetes, in which an amelioration of cardiac remodeling and ECM was evident. In both settings, SBECD + OTX + CHR was the most effective treatment compared to the other ones. Conclusion: The CHR-based supramolecular SBECD-calixarene drug delivery system, by enhancing the solubility and the bioavailability of both CHR and calixarene OTX008, and by combining their effects, showed a strong anti-fibrotic activity in rat cardiomyocytes and in cardiac tissue from mice with chronic diabetes. Also an improved cardiac tissue remodeling was evident. Therefore, new drug delivery system, which could be considered as a novel putative therapeutic strategy for the treatment of diabetes-induced cardiac fibrosis.
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Affiliation(s)
- Maria Consiglia Trotta
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Hildegard Herman
- “Aurel Ardelean” Institute of Life Sciences, Vasile Goldis Western University of Arad, Arad, Romania
| | - Alina Ciceu
- “Aurel Ardelean” Institute of Life Sciences, Vasile Goldis Western University of Arad, Arad, Romania
| | - Bianca Mladin
- “Aurel Ardelean” Institute of Life Sciences, Vasile Goldis Western University of Arad, Arad, Romania
| | - Marcel Rosu
- “Aurel Ardelean” Institute of Life Sciences, Vasile Goldis Western University of Arad, Arad, Romania
| | - Caterina Claudia Lepre
- “Aurel Ardelean” Institute of Life Sciences, Vasile Goldis Western University of Arad, Arad, Romania
- PhD Course in Translational Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Marina Russo
- PhD Course in National Interest in Public Administration and Innovation for Disability and Social Inclusion, Department of Mental, Physical Health and Preventive Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy
- School of Pharmacology and Clinical Toxicology, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Ildikó Bácskay
- Department of Molecular and Nanopharmaceutics, Faculty of Pharmacy, University of Debrecen, Debrecen, Hungary
- Institute of Healthcare Industry, University of Debrecen, Debrecen, Hungary
| | - Ferenc Fenyvesi
- Department of Molecular and Nanopharmaceutics, Faculty of Pharmacy, University of Debrecen, Debrecen, Hungary
| | - Raffaele Marfella
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Anca Hermenean
- “Aurel Ardelean” Institute of Life Sciences, Vasile Goldis Western University of Arad, Arad, Romania
- Department of Histology, Faculty of Medicine, Vasile Goldis Western University of Arad, Arad, Romania
| | - Cornel Balta
- “Aurel Ardelean” Institute of Life Sciences, Vasile Goldis Western University of Arad, Arad, Romania
| | - Michele D’Amico
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy
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17
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Sharma A, De Blasio M, Ritchie R. Current challenges in the treatment of cardiac fibrosis: Recent insights into the sex-specific differences of glucose-lowering therapies on the diabetic heart: IUPHAR Review 33. Br J Pharmacol 2023; 180:2916-2933. [PMID: 35174479 PMCID: PMC10952904 DOI: 10.1111/bph.15820] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 01/13/2022] [Accepted: 01/18/2022] [Indexed: 11/28/2022] Open
Abstract
A significant cardiac complication of diabetes is cardiomyopathy, a form of ventricular dysfunction that develops independently of coronary artery disease, hypertension and valvular diseases, which may subsequently lead to heart failure. Several structural features underlie the development of diabetic cardiomyopathy and eventual diabetes-induced heart failure. Pathological cardiac fibrosis (interstitial and perivascular), in addition to capillary rarefaction and myocardial apoptosis, are particularly noteworthy. Sex differences in the incidence, development and presentation of diabetes, heart failure and interstitial myocardial fibrosis have been identified. Nevertheless, therapeutics specifically targeting diabetes-associated cardiac fibrosis remain lacking and treatment approaches remain the same regardless of patient sex or the co-morbidities that patients may present. This review addresses the observed anti-fibrotic effects of newer glucose-lowering therapies and traditional cardiovascular disease treatments, in the diabetic myocardium (from both preclinical and clinical contexts). Furthermore, any known sex differences in these treatment effects are also explored. LINKED ARTICLES: This article is part of a themed issue on Translational Advances in Fibrosis as a Therapeutic Target. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.22/issuetoc.
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Affiliation(s)
- Abhipree Sharma
- Heart Failure Pharmacology, Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences (MIPS)Monash UniversityParkvilleVictoriaAustralia
| | - Miles De Blasio
- Heart Failure Pharmacology, Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences (MIPS)Monash UniversityParkvilleVictoriaAustralia
- Department of PharmacologyMonash UniversityClaytonVictoriaAustralia
| | - Rebecca Ritchie
- Heart Failure Pharmacology, Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences (MIPS)Monash UniversityParkvilleVictoriaAustralia
- Department of PharmacologyMonash UniversityClaytonVictoriaAustralia
- Department of MedicineMonash UniversityClaytonVictoriaAustralia
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18
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Cohen CD, De Blasio MJ, Farrugia GE, Dona MS, Hsu I, Prakoso D, Kiriazis H, Krstevski C, Nash DM, Li M, Gaynor TL, Deo M, Drummond GR, Ritchie RH, Pinto AR. Mapping the cellular and molecular landscape of cardiac non-myocytes in murine diabetic cardiomyopathy. iScience 2023; 26:107759. [PMID: 37736052 PMCID: PMC10509303 DOI: 10.1016/j.isci.2023.107759] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 05/01/2023] [Accepted: 08/25/2023] [Indexed: 09/23/2023] Open
Abstract
Diabetes is associated with a significantly elevated risk of heart failure. However, despite extensive efforts to characterize the phenotype of the diabetic heart, the molecular and cellular protagonists that underpin cardiac pathological remodeling in diabetes remain unclear, with a notable paucity of data regarding the impact of diabetes on non-myocytes within the heart. Here we aimed to define key differences in cardiac non-myocytes between spontaneously type-2 diabetic (db/db) and healthy control (db/h) mouse hearts. Single-cell transcriptomic analysis revealed a concerted diabetes-induced cellular response contributing to cardiac remodeling. These included cell-specific activation of gene programs relating to fibroblast hyperplasia and cell migration, and dysregulation of pathways involving vascular homeostasis and protein folding. This work offers a new perspective for understanding the cellular mediators of diabetes-induced cardiac pathology, and pathways that may be targeted to address the cardiac complications associated with diabetes.
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Affiliation(s)
- Charles D. Cohen
- Cardiac Cellular Systems, Baker Heart and Diabetes Institute, Prahran, VIC, Australia
- Heart Failure Pharmacology, Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, Australia
- Department of Microbiology, Anatomy, Physiology and Pharmacology, La Trobe University, Bundoora, VIC, Australia
- Centre for Cardiovascular Biology and Disease Research, La Trobe University, Melbourne, VIC, Australia
| | - Miles J. De Blasio
- Heart Failure Pharmacology, Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, Australia
- Department of Pharmacology, Monash University, Clayton, VIC, Australia
| | - Gabriella E. Farrugia
- Cardiac Cellular Systems, Baker Heart and Diabetes Institute, Prahran, VIC, Australia
- Baker Department of Cardiovascular Research and Implementation, La Trobe University, Melbourne, VIC, Australia
| | - Malathi S.I. Dona
- Cardiac Cellular Systems, Baker Heart and Diabetes Institute, Prahran, VIC, Australia
| | - Ian Hsu
- Cardiac Cellular Systems, Baker Heart and Diabetes Institute, Prahran, VIC, Australia
| | - Darnel Prakoso
- Heart Failure Pharmacology, Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, Australia
| | - Helen Kiriazis
- Preclinical Cardiology, Microsurgery and Imaging Platform, Baker Heart and Diabetes Institute, Prahran, VIC, Australia
- Baker Department of Cardiometabolic Health, University of Melbourne, Parkville, VIC, Australia
| | - Crisdion Krstevski
- Cardiac Cellular Systems, Baker Heart and Diabetes Institute, Prahran, VIC, Australia
- Department of Microbiology, Anatomy, Physiology and Pharmacology, La Trobe University, Bundoora, VIC, Australia
- Centre for Cardiovascular Biology and Disease Research, La Trobe University, Melbourne, VIC, Australia
| | - David M. Nash
- Heart Failure Pharmacology, Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, Australia
| | - Mandy Li
- Heart Failure Pharmacology, Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, Australia
| | - Taylah L. Gaynor
- Cardiac Cellular Systems, Baker Heart and Diabetes Institute, Prahran, VIC, Australia
- Department of Microbiology, Anatomy, Physiology and Pharmacology, La Trobe University, Bundoora, VIC, Australia
- Centre for Cardiovascular Biology and Disease Research, La Trobe University, Melbourne, VIC, Australia
| | - Minh Deo
- Heart Failure Pharmacology, Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, Australia
| | - Grant R. Drummond
- Centre for Cardiovascular Biology and Disease Research, La Trobe University, Melbourne, VIC, Australia
| | - Rebecca H. Ritchie
- Heart Failure Pharmacology, Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, Australia
- Department of Microbiology, Anatomy, Physiology and Pharmacology, La Trobe University, Bundoora, VIC, Australia
- Centre for Cardiovascular Biology and Disease Research, La Trobe University, Melbourne, VIC, Australia
| | - Alexander R. Pinto
- Cardiac Cellular Systems, Baker Heart and Diabetes Institute, Prahran, VIC, Australia
- Department of Microbiology, Anatomy, Physiology and Pharmacology, La Trobe University, Bundoora, VIC, Australia
- Centre for Cardiovascular Biology and Disease Research, La Trobe University, Melbourne, VIC, Australia
- Baker Department of Cardiometabolic Health, University of Melbourne, Parkville, VIC, Australia
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19
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Yu Y, Tong D, Yu Y, Tian D, Zhou W, Zhang X, Shi W, Liu G. Toxic effects of four emerging pollutants on cardiac performance and associated physiological parameters of the thick-shell mussel (Mytilus coruscus). ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2023; 334:122244. [PMID: 37482340 DOI: 10.1016/j.envpol.2023.122244] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Revised: 07/01/2023] [Accepted: 07/20/2023] [Indexed: 07/25/2023]
Abstract
Robust cardiac performance is critical for the health and even survival of an animal; however, it is sensitive to environmental stressors. At present, little is known about the cardiotoxicity of emerging pollutants to bivalve mollusks. Thus, in this study, the cardiotoxic effects of four emergent pollutants, carbamazepine (CBZ), bisphenol A (BPA), tetrabromobisphenol A (TBBPA), and tris(2-chloroethyl) phosphate (TCEP), on the thick-shell mussel, Mytilus coruscus, were evaluated by heartbeat monitoring and histological examinations. In addition, the impacts of these pollutants on parameters that closely related to cardiac function including neurotransmitters, calcium homeostasis, energy supply, and oxidative status were assessed. Our results demonstrated that 28-day exposure of the thick-shell mussel to these pollutants resulted in evident heart tissue lesions (indicated by hemocyte infiltration and myocardial fibrosis) and disruptions of cardiac performance (characterized by bradyrhythmia and arrhythmia). In addition to obstructing neurotransmitters and calcium homeostasis, exposure to pollutants also led to constrained energy supply and induced oxidative stress in mussel hearts. These findings indicate that although do differ somehow in their effects, these four pollutants may exert cardiotoxic impacts on mussels, which could pose severe threats to this important species and therefore deserves more attention.
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Affiliation(s)
- Yingying Yu
- College of Animal Sciences, Zhejiang University, Hangzhou, PR China
| | - Difei Tong
- College of Animal Sciences, Zhejiang University, Hangzhou, PR China
| | - Yihan Yu
- College of Animal Sciences, Zhejiang University, Hangzhou, PR China
| | - Dandan Tian
- College of Animal Sciences, Zhejiang University, Hangzhou, PR China
| | - Weishang Zhou
- College of Animal Sciences, Zhejiang University, Hangzhou, PR China
| | - Xunyi Zhang
- College of Animal Sciences, Zhejiang University, Hangzhou, PR China
| | - Wei Shi
- College of Animal Sciences, Zhejiang University, Hangzhou, PR China
| | - Guangxu Liu
- College of Animal Sciences, Zhejiang University, Hangzhou, PR China.
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20
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Zhao X, Huang B, Zhang J, Xiang W, Zhu N. Celastrol attenuates streptozotocin-induced diabetic cardiomyopathy in mice by inhibiting the ACE / Ang II / AGTR1 signaling pathway. Diabetol Metab Syndr 2023; 15:186. [PMID: 37700366 PMCID: PMC10496318 DOI: 10.1186/s13098-023-01159-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Accepted: 09/04/2023] [Indexed: 09/14/2023] Open
Abstract
BACKGROUND Heart failure is closely correlated with diabetic cardiomyopathy (DCM) and can lead to mortality. Celastrol has long been utilized for the treatment of immune and inflammatory disorders. However, whether celastrol would exert protective effects on DCM has not been determined. This work aimed to explore the protective actions of celastrol on DCM and unravel the underlying mechanisms involved. METHODS A DCM model was constructed in mice by intraperitoneal administration of streptozotocin. ELISA and echocardiography were performed to examine myocardial injury markers and cardiac function, respectively. Morphological changes and fibrosis were assessed using H&E staining and Masson's staining. Inflammatory cytokines and fibrotic markers were detected by ELISA and RT-PCR. Endothelial nitric oxide synthase, apoptosis, and reactive oxygen species were detected by microscopic staining. Network pharmacology approaches, molecular docking analysis, ELISA, and Western blot were used for mechanism studies. RESULTS Celastrol alleviated diabetes-induced cardiac injury and remodeling. Celastrol also suppressed diabetes-induced production of inflammatory cytokines and reactive oxygen species, as well as cardiomyocyte apoptosis. The cardioprotective effects of celastrol were associated with its inhibition on the angiotensin-converting enzyme / angiotensin II / angiotensin II receptor type 1 signaling pathway. CONCLUSION Celastrol exhibits significant potential as an effective cardioprotective drug for DCM treatment. The underlying mechanisms can be attributed to the blockage of celastrol on the angiotensin-converting enzyme signaling pathway.
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Affiliation(s)
- Xuyong Zhao
- Department of Cardiology, The Wenzhou Third Clinical Institute, The Third Affiliated Hospital of Shanghai University, Wenzhou Medical University, Wenzhou People's Hospital, No. 299 Guan Road, Wenzhou, Zhejiang Province, People's Republic of China
| | - Bingwu Huang
- Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital, Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Jianhua Zhang
- Department of Cardiology, The Wenzhou Third Clinical Institute, The Third Affiliated Hospital of Shanghai University, Wenzhou Medical University, Wenzhou People's Hospital, No. 299 Guan Road, Wenzhou, Zhejiang Province, People's Republic of China
| | - Wenjun Xiang
- Department of Pathology, The Wenzhou Third Clinical Institute, The Third Affiliated Hospital of Shanghai University, Wenzhou Medical University, Wenzhou People's Hospital, Wenzhou, China
| | - Ning Zhu
- Department of Cardiology, The Wenzhou Third Clinical Institute, The Third Affiliated Hospital of Shanghai University, Wenzhou Medical University, Wenzhou People's Hospital, No. 299 Guan Road, Wenzhou, Zhejiang Province, People's Republic of China.
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21
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Pu TT, Wu W, Liang PD, Du JC, Han SL, Deng XL, Du XJ. Evaluation of Coenzyme Q10 (CoQ10) Deficiency and Therapy in Mouse Models of Cardiomyopathy. J Cardiovasc Pharmacol 2023; 81:259-269. [PMID: 36668724 PMCID: PMC10079299 DOI: 10.1097/fjc.0000000000001401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 01/07/2023] [Indexed: 01/22/2023]
Abstract
ABSTRACT Mitochondrial dysfunction plays a key role in the development of heart failure, but targeted therapeutic interventions remain elusive. Previous studies have shown coenzyme Q10 (CoQ10) insufficiency in patients with heart disease with undefined mechanism and modest effectiveness of CoQ10 supplement therapy. Using 2 transgenic mouse models of cardiomyopathy owing to cardiac overexpression of Mst1 (Mst1-TG) or β 2 -adrenoceptor (β 2 AR-TG), we studied changes in cardiac CoQ10 content and alterations in CoQ10 biosynthesis genes. We also studied in Mst1-TG mice effects of CoQ10, delivered by oral or injection regimens, on both cardiac CoQ10 content and cardiomyopathy phenotypes. High performance liquid chromatography and RNA sequencing revealed in both models significant reduction in cardiac content of CoQ10 and downregulation of most genes encoding CoQ10 biosynthesis enzymes. Mst1-TG mice with 70% reduction in cardiac CoQ10 were treated with CoQ10 either by oral gavage or i.p. injection for 4-8 weeks. Oral regimens failed in increasing cardiac CoQ10 content, whereas injection regimen effectively restored the cardiac CoQ10 level in a time-dependent manner. However, CoQ10 restoration in Mst1-TG mice did not correct mitochondrial dysfunction measured by energy metabolism, downregulated expression of marker proteins, and oxidative stress nor to preserve cardiac contractile function. In conclusion, mouse models of cardiomyopathy exhibited myocardial CoQ10 deficiency likely due to suppressed endogenous synthesis of CoQ10. In contrast to ineffectiveness of oral administration, CoQ10 administration by injection regimen in cardiomyopathy mice restored cardiac CoQ10 content, which, however, failed in achieving detectable efficacy at molecular and global functional levels.
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Affiliation(s)
- Tian-Tian Pu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Health Science Center, Xian Jiaotong University, Xi'an, China; and
| | - Wei Wu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Health Science Center, Xian Jiaotong University, Xi'an, China; and
| | - Pei-Da Liang
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, China
| | - Jin-Chan Du
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Health Science Center, Xian Jiaotong University, Xi'an, China; and
| | - Sheng-Li Han
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, China
| | - Xiu-Ling Deng
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Health Science Center, Xian Jiaotong University, Xi'an, China; and
| | - Xiao-Jun Du
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Health Science Center, Xian Jiaotong University, Xi'an, China; and
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22
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Bojer AS, Sørensen MH, Madsen SH, Broadbent DA, Plein S, Gæde P, Madsen PL. The independent association of myocardial extracellular volume and myocardial blood flow with cardiac diastolic function in patients with type 2 diabetes: a prospective cross-sectional cohort study. Cardiovasc Diabetol 2023; 22:78. [PMID: 37004049 PMCID: PMC10067250 DOI: 10.1186/s12933-023-01804-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Accepted: 03/16/2023] [Indexed: 04/03/2023] Open
Abstract
BACKGROUND Diffuse myocardial fibrosis and microvascular dysfunction are suggested to underlie cardiac dysfunction in patients with type 2 diabetes, but studies investigating their relative impact are lacking. We aimed to study imaging biomarkers of these and hypothesized that fibrosis and microvascular dysfunction would affect different phases of left ventricular (LV) diastole. METHODS In this cross-sectional study myocardial blood flow (MBF) at rest and adenosine-stress and perfusion reserve (MPR), as well as extracellular volume fraction (ECV), were determined with cardiovascular magnetic resonance (CMR) imaging in 205 patients with type 2 diabetes and 25 controls. Diastolic parameters included echocardiography-determined lateral e' and average E/e', and CMR-determined (rest and chronotropic-stress) LV early peak filling rate (ePFR), LV peak diastolic strain rate (PDSR), and left atrial (LA) volume changes. RESULTS In multivariable analysis adjusted for possible confounders including each other (ECV for blood flow and vice versa), a 10% increase of ECV was independently associated with ePFR/EDV (rest: β = - 4.0%, stress: β = - 7.9%), LAmax /BSA (rest: β = 4.8%, stress: β = 5.8%), and circumferential (β = - 4.1%) and radial PDSR (β = 0.07%/sec). A 10% stress MBF increase was associated with lateral e' (β = 1.4%) and average E/e' (β = - 1.4%) and a 10% MPR increase to lateral e' (β = 2.7%), and average E/e' (β = - 2.8%). For all the above, p < 0.05. No associations were found with longitudinal PDSR or left atrial total emptying fraction. CONCLUSION In patients with type 2 diabetes, imaging biomarkers of microvascular dysfunction and diffuse fibrosis impacts diastolic dysfunction independently of each other. Microvascular dysfunction primarily affects early left ventricular relaxation. Diffuse fibrosis primarily affects diastasis. Trial registration https://www. CLINICALTRIALS gov . Unique identifier: NCT02684331. Date of registration: February 18, 2016.
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Affiliation(s)
- Annemie S Bojer
- Department of Cardiology and Endocrinology, Slagelse Hospital, Ingemannsvej 32, Region Zealand, 4200, Slagelse, Denmark.
- Institute of Regional Health Research, Faculty of Health Sciences, University of Southern, Odense, Denmark.
| | - Martin H Sørensen
- Department of Cardiology and Endocrinology, Slagelse Hospital, Ingemannsvej 32, Region Zealand, 4200, Slagelse, Denmark
| | - Stine H Madsen
- Department of Cardiology, Copenhagen University Hospital Herlev-Gentofte, Capital Region of Denmark, Hellerup, Denmark
| | - David A Broadbent
- Department of Medical Physics and Engineering, Leeds Teaching Hospitals NHS Trust, Leeds, UK
- Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK
| | - Sven Plein
- Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK
| | - Peter Gæde
- Department of Cardiology and Endocrinology, Slagelse Hospital, Ingemannsvej 32, Region Zealand, 4200, Slagelse, Denmark
- Institute of Regional Health Research, Faculty of Health Sciences, University of Southern, Odense, Denmark
| | - Per L Madsen
- Department of Cardiology, Copenhagen University Hospital Herlev-Gentofte, Capital Region of Denmark, Hellerup, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
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23
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Emerging Therapy for Diabetic Cardiomyopathy: From Molecular Mechanism to Clinical Practice. Biomedicines 2023; 11:biomedicines11030662. [PMID: 36979641 PMCID: PMC10045486 DOI: 10.3390/biomedicines11030662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 02/08/2023] [Accepted: 02/11/2023] [Indexed: 02/24/2023] Open
Abstract
Diabetic cardiomyopathy is characterized by abnormal myocardial structure or performance in the absence of coronary artery disease or significant valvular heart disease in patients with diabetes mellitus. The spectrum of diabetic cardiomyopathy ranges from subtle myocardial changes to myocardial fibrosis and diastolic function and finally to symptomatic heart failure. Except for sodium–glucose transport protein 2 inhibitors and possibly bariatric and metabolic surgery, there is currently no specific treatment for this distinct disease entity in patients with diabetes. The molecular mechanism of diabetic cardiomyopathy includes impaired nutrient-sensing signaling, dysregulated autophagy, impaired mitochondrial energetics, altered fuel utilization, oxidative stress and lipid peroxidation, advanced glycation end-products, inflammation, impaired calcium homeostasis, abnormal endothelial function and nitric oxide production, aberrant epidermal growth factor receptor signaling, the activation of the renin–angiotensin–aldosterone system and sympathetic hyperactivity, and extracellular matrix accumulation and fibrosis. Here, we summarize several important emerging treatments for diabetic cardiomyopathy targeting specific molecular mechanisms, with evidence from preclinical studies and clinical trials.
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24
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Mthembu SXH, Orlando P, Silvestri S, Ziqubu K, Mazibuko-Mbeje SE, Mabhida SE, Nyambuya TM, Nkambule BB, Muller CJF, Basson AK, Tiano L, Dludla PV. Impact of dyslipidemia in the development of cardiovascular complications: Delineating the potential therapeutic role of coenzyme Q 10. Biochimie 2023; 204:33-40. [PMID: 36067903 DOI: 10.1016/j.biochi.2022.08.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 08/23/2022] [Accepted: 08/29/2022] [Indexed: 01/12/2023]
Abstract
Dyslipidemia is one of the major risk factors for the development of cardiovascular disease (CVD) in patients with type 2 diabetes (T2D). This metabolic anomality is implicated in the generation of oxidative stress, an inevitable process involved in destructive mechanisms leading to myocardial damage. Fortunately, commonly used drugs like statins can counteract the detrimental effects of dyslipidemia by lowering cholesterol to reduce CVD-risk in patients with T2D. Statins mainly function by blocking the production of cholesterol by targeting the mevalonate pathway. However, by blocking cholesterol synthesis, statins coincidently inhibit the synthesis of other essential isoprenoid intermediates of the mevalonate pathway like farnesyl pyrophosphate and coenzyme Q10 (CoQ10). The latter is by far the most important co-factor and co-enzyme required for efficient mitochondrial oxidative capacity, in addition to its robust antioxidant properties. In fact, supplementation with CoQ10 has been found to be beneficial in ameliorating oxidative stress and improving blood flow in subjects with mild dyslipidemia.. Beyond discussing the destructive effects of oxidative stress in dyslipidemia-induced CVD-related complications, the current review brings a unique perspective in exploring the mevalonate pathway to block cholesterol synthesis while enhancing or maintaining CoQ10 levels in conditions of dyslipidemia. Furthermore, this review disscusses the therapeutic potential of bioactive compounds in targeting the downstream of the mevalonate pathway, more importantly, their ability to block cholesterol while maintaining CoQ10 biosynthesis to protect against the destructive complications of dyslipidemia.
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Affiliation(s)
- Sinenhlanhla X H Mthembu
- Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg, 7505, South Africa; Department of Biochemistry, Mafikeng Campus, Northwest University, Mmabatho, 2735, South Africa
| | - Patrick Orlando
- Department of Life and Environmental Sciences, Polytechnic University of Marche, Ancona, 60131, Italy
| | - Sonia Silvestri
- Department of Life and Environmental Sciences, Polytechnic University of Marche, Ancona, 60131, Italy
| | - Khanyisani Ziqubu
- Department of Biochemistry, Mafikeng Campus, Northwest University, Mmabatho, 2735, South Africa
| | | | - Sihle E Mabhida
- Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg, 7505, South Africa
| | - Tawanda M Nyambuya
- Department of Health Sciences, Namibia University of Science and Technology, Windhoek, 9000, Namibia
| | - Bongani B Nkambule
- School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, 4000, South Africa
| | - Christo J F Muller
- Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg, 7505, South Africa; Centre for Cardiometabolic Research Africa (CARMA), Division of Medical Physiology, Stellenbosch University, Tygerberg, 7505, South Africa; Department of Biochemistry and Microbiology, University of Zululand, KwaDlangezwa, 3886, South Africa
| | - Albertus K Basson
- Department of Biochemistry and Microbiology, University of Zululand, KwaDlangezwa, 3886, South Africa
| | - Luca Tiano
- Department of Life and Environmental Sciences, Polytechnic University of Marche, Ancona, 60131, Italy
| | - Phiwayinkosi V Dludla
- Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg, 7505, South Africa.
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25
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Dhar A, Venkadakrishnan J, Roy U, Vedam S, Lalwani N, Ramos KS, Pandita TK, Bhat A. A comprehensive review of the novel therapeutic targets for the treatment of diabetic cardiomyopathy. Ther Adv Cardiovasc Dis 2023; 17:17539447231210170. [PMID: 38069578 PMCID: PMC10710750 DOI: 10.1177/17539447231210170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 10/09/2023] [Indexed: 12/18/2023] Open
Abstract
Diabetic cardiomyopathy (DCM) is characterized by structural and functional abnormalities in the myocardium affecting people with diabetes. Treatment of DCM focuses on glucose control, blood pressure management, lipid-lowering, and lifestyle changes. Due to limited therapeutic options, DCM remains a significant cause of morbidity and mortality in patients with diabetes, thus emphasizing the need to develop new therapeutic strategies. Ongoing research is aimed at understanding the underlying molecular mechanism(s) involved in the development and progression of DCM, including oxidative stress, inflammation, and metabolic dysregulation. The goal is to develope innovative pharmaceutical therapeutics, offering significant improvements in the clinical management of DCM. Some of these approaches include the effective targeting of impaired insulin signaling, cardiac stiffness, glucotoxicity, lipotoxicity, inflammation, oxidative stress, cardiac hypertrophy, and fibrosis. This review focuses on the latest developments in understanding the underlying causes of DCM and the therapeutic landscape of DCM treatment.
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Affiliation(s)
- Arti Dhar
- Department of Pharmacy, Birla Institute of Technology and Science Pilani, Hyderabad, Telangana, India
| | | | - Utsa Roy
- Department of Pharmacy, Birla Institute of Technology and Science Pilani, Hyderabad, Telangana, India
| | - Sahithi Vedam
- Department of Pharmacy, Birla Institute of Technology and Science Pilani, Hyderabad, Telangana, India
| | - Nikita Lalwani
- Department of Pharmacy, Birla Institute of Technology and Science Pilani, Hyderabad, Telangana, India
| | - Kenneth S. Ramos
- Center for Genomics and Precision Medicine, Texas A&M College of Medicine, Houston, TX 77030, USA
| | - Tej K. Pandita
- Center for Genomics and Precision Medicine, Texas A&M College of Medicine, Houston, TX 77030, USA
| | - Audesh Bhat
- Centre for Molecular Biology, Central University of Jammu, Samba, Jammu and Kashmir (UT) 184311, India
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26
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Prakoso D, De Blasio MJ, Tate M, Ritchie RH. Current landscape of preclinical models of diabetic cardiomyopathy. Trends Pharmacol Sci 2022; 43:940-956. [PMID: 35779966 DOI: 10.1016/j.tips.2022.04.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 04/04/2022] [Accepted: 04/11/2022] [Indexed: 12/01/2022]
Abstract
Patients with diabetes have an increased risk of developing heart failure, preceded by (often asymptomatic) cardiac abnormalities, collectively called diabetic cardiomyopathy (DC). Diabetic heart failure lacks effective treatment, remaining an urgent, unmet clinical need. Although structural and functional characteristics of the diabetic human heart are well defined, clinical studies lack the ability to pinpoint the specific mechanisms responsible for DC. Preclinical animal models represent a vital component for understanding disease aetiology, which is essential for the discovery of new targeted treatments for diabetes-induced heart failure. In this review, we describe the current landscape of preclinical DC models (genetic, pharmacologically induced, and diet-induced models), highlighting their strengths and weaknesses and alignment to features of the human disease. Finally, we provide tools, resources, and recommendations to assist future preclinical translation addressing this knowledge gap.
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Affiliation(s)
- Darnel Prakoso
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia
| | - Miles J De Blasio
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia; Department of Pharmacology, Monash University, Clayton, VIC 3800, Australia
| | - Mitchel Tate
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia
| | - Rebecca H Ritchie
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia; Department of Pharmacology, Monash University, Clayton, VIC 3800, Australia; Department of Diabetes, Monash University, Clayton, VIC 3800, Australia.
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27
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He J, Li Z, Xia P, Shi A, FuChen X, Zhang J, Yu P. Ferroptosis and ferritinophagy in diabetes complications. Mol Metab 2022; 60:101470. [PMID: 35304332 PMCID: PMC8980341 DOI: 10.1016/j.molmet.2022.101470] [Citation(s) in RCA: 88] [Impact Index Per Article: 29.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 02/26/2022] [Accepted: 03/03/2022] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND With long-term metabolic malfunction, diabetes can cause serious damage to whole-body tissue and organs, resulting in a variety of complications. Therefore, it is particularly important to further explore the pathogenesis of diabetes complications and develop drugs for prevention and treatment. In recent years, different from apoptosis and necrosis, ferroptosis has been recognized as a new regulatory mode of cell death and involves the regulation of nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy. Evidence shows that ferroptosis and ferritinophagy play a significant role in the occurrence and development of diabetes complications. SCOPE OF REVIEW we systematically review the current understanding of ferroptosis and ferritinophagy, focusing on their potential mechanisms, connection, and regulation, discuss their involvement in diabetes complications, and consider emerging therapeutic opportunities and the associated challenges with future prospects. MAJOR CONCLUSIONS In summary, ferroptosis and ferritinophagy are worthy targets for the treatment of diabetes complications, but their complete molecular mechanism and pathophysiological process still require further study.
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Affiliation(s)
- Jiahui He
- The Second Clinical Medical College of Nanchang University, The Second Affiliated Hospital of Nanchang University, Jiangxi, Nanchang 330006, China
| | - Zhangwang Li
- The Second Clinical Medical College of Nanchang University, The Second Affiliated Hospital of Nanchang University, Jiangxi, Nanchang 330006, China
| | - Panpan Xia
- The Second Clinical Medical College of Nanchang University, The Second Affiliated Hospital of Nanchang University, Jiangxi, Nanchang 330006, China; Department of Metabolism and Endocrinology, The Second Affiliated Hospital of Nanchang University, Jiangxi, Nanchang 330006, China
| | - Ao Shi
- School of Medicine, St. George University of London, London, UK; School of Medicine, University of Nicosia, Nicosia, Cyprus
| | - Xinxi FuChen
- The Second Clinical Medical College of Nanchang University, The Second Affiliated Hospital of Nanchang University, Jiangxi, Nanchang 330006, China; Department of Metabolism and Endocrinology, The Second Affiliated Hospital of Nanchang University, Jiangxi, Nanchang 330006, China
| | - Jing Zhang
- The Second Clinical Medical College of Nanchang University, The Second Affiliated Hospital of Nanchang University, Jiangxi, Nanchang 330006, China; Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Jiangxi, Nanchang 30006, China.
| | - Peng Yu
- The Second Clinical Medical College of Nanchang University, The Second Affiliated Hospital of Nanchang University, Jiangxi, Nanchang 330006, China; Department of Metabolism and Endocrinology, The Second Affiliated Hospital of Nanchang University, Jiangxi, Nanchang 330006, China.
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28
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Guo Y, Zhang W, Zhou X, Zhao S, Wang J, Guo Y, Liao Y, Lu H, Liu J, Cai Y, Wu J, Shen M. Roles of Ferroptosis in Cardiovascular Diseases. Front Cardiovasc Med 2022; 9:911564. [PMID: 35677693 PMCID: PMC9168067 DOI: 10.3389/fcvm.2022.911564] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Accepted: 05/02/2022] [Indexed: 12/14/2022] Open
Abstract
Ferroptosis is an iron-dependent regulated cell death characterized by lipid peroxidation and iron overload, which is different from other types of programmed cell death, including apoptosis, necroptosis, autophagy, and pyroptosis. Over the past years, emerging studies have shown a close relation between ferroptosis and various cardiovascular diseases such as atherosclerosis, acute myocardial infarction, ischemia/reperfusion injury, cardiomyopathy, and heart failure. Herein, we will review the contributions of ferroptosis to multiple cardiovascular diseases and the related targets. Further, we discuss the potential ferroptosis-targeting strategies for treating different cardiovascular diseases.
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Affiliation(s)
- Yuting Guo
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
- Department of Cardiology, Hainan Hospital of Chinese PLA General Hosptial, Hainan Geriatric Disease Clinical Medical Research Center, Hainan Branch of China Geriatric Disease Clinical Research Center, Hainan, China
| | - Wei Zhang
- Department of Cardiology, Second Medical Center, PLA General Hospital, Beijing, China
| | - Xinger Zhou
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
- Department of Cardiology, Hainan Hospital of Chinese PLA General Hosptial, Hainan Geriatric Disease Clinical Medical Research Center, Hainan Branch of China Geriatric Disease Clinical Research Center, Hainan, China
| | - Shihao Zhao
- Department of Cardiology, Hainan Hospital of Chinese PLA General Hosptial, Hainan Geriatric Disease Clinical Medical Research Center, Hainan Branch of China Geriatric Disease Clinical Research Center, Hainan, China
| | - Jian Wang
- Department of Cardiology, Hainan Hospital of Chinese PLA General Hosptial, Hainan Geriatric Disease Clinical Medical Research Center, Hainan Branch of China Geriatric Disease Clinical Research Center, Hainan, China
| | - Yi Guo
- Department of Cardiology, Hainan Hospital of Chinese PLA General Hosptial, Hainan Geriatric Disease Clinical Medical Research Center, Hainan Branch of China Geriatric Disease Clinical Research Center, Hainan, China
| | - Yichao Liao
- Department of Cardiology, Hainan Hospital of Chinese PLA General Hosptial, Hainan Geriatric Disease Clinical Medical Research Center, Hainan Branch of China Geriatric Disease Clinical Research Center, Hainan, China
| | - Haihui Lu
- Department of Cardiology, Hainan Hospital of Chinese PLA General Hosptial, Hainan Geriatric Disease Clinical Medical Research Center, Hainan Branch of China Geriatric Disease Clinical Research Center, Hainan, China
| | - Jie Liu
- Department of Cardiology, Hainan Hospital of Chinese PLA General Hosptial, Hainan Geriatric Disease Clinical Medical Research Center, Hainan Branch of China Geriatric Disease Clinical Research Center, Hainan, China
| | - Yanbin Cai
- Department of Cardiology and Laboratory of Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Jiao Wu
- Department of Cell Biology, National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an, China
- Jiao Wu
| | - Mingzhi Shen
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
- Department of Cardiology, Hainan Hospital of Chinese PLA General Hosptial, Hainan Geriatric Disease Clinical Medical Research Center, Hainan Branch of China Geriatric Disease Clinical Research Center, Hainan, China
- *Correspondence: Mingzhi Shen
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Diabetes and Myocardial Fibrosis: A Systematic Review and Meta-Analysis. JACC. CARDIOVASCULAR IMAGING 2022; 15:796-808. [PMID: 35512952 DOI: 10.1016/j.jcmg.2021.12.008] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 11/23/2021] [Accepted: 12/15/2021] [Indexed: 12/23/2022]
Abstract
OBJECTIVES This systematic review and meta-analysis investigated the association of diabetes and glycemic control with myocardial fibrosis (MF). BACKGROUND MF is associated with an increased risk of heart failure, coronary artery disease, arrhythmias, and death. Diabetes may influence the development of MF, but evidence is inconsistent. METHODS The authors searched EMBASE, Medline Ovid, Cochrane CENTRAL, Web of Science, and Google Scholar for observational and interventional studies investigating the association of diabetes, glycemic control, and antidiabetic medication with MF assessed by histology and cardiac magnetic resonance (ie, extracellular volume fraction [ECV%] and T1 time). RESULTS A total of 32 studies (88% exclusively on type 2 diabetes) involving 5,053 participants were included in the systematic review. Meta-analyses showed that diabetes was associated with a higher degree of MF assessed by histological collagen volume fraction (n = 6 studies; mean difference: 5.80; 95% CI: 2.00-9.59) and ECV% (13 studies; mean difference: 2.09; 95% CI: 0.92-3.27), but not by native or postcontrast T1 time. Higher glycosylated hemoglobin levels were associated with higher degrees of MF. CONCLUSIONS Diabetes is associated with higher degree of MF assessed by histology and ECV% but not by T1 time. In patients with diabetes, worse glycemic control was associated with higher MF degrees. These findings mostly apply to type 2 diabetes and warrant further investigation into whether these associations are causal and which medications could attenuate MF in patients with diabetes.
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Dugbartey GJ, Wonje QL, Alornyo KK, Robertson L, Adams I, Boima V, Mensah SD. Combination Therapy of Alpha-Lipoic Acid, Gliclazide and Ramipril Protects Against Development of Diabetic Cardiomyopathy via Inhibition of TGF-β/Smad Pathway. Front Pharmacol 2022; 13:850542. [PMID: 35401218 PMCID: PMC8988231 DOI: 10.3389/fphar.2022.850542] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Accepted: 02/21/2022] [Indexed: 12/17/2022] Open
Abstract
Background: Diabetic cardiomyopathy (DCM) is a major long-term complication of diabetes mellitus, accounting for over 20% of annual mortality rate of diabetic patients globally. Although several existing anti-diabetic drugs have improved glycemic status in diabetic patients, prevalence of DCM is still high. This study investigates cardiac effect of alpha-lipoic acid (ALA) supplementation of anti-diabetic therapy in experimental DCM. Methods: Following 12 h of overnight fasting, 44 male Sprague Dawley rats were randomly assigned to two groups of healthy control (n = 7) and diabetic (n = 37) groups, and fasting blood glucose was measured. Type 2 diabetes mellitus (T2DM) was induced in diabetic group by intraperitoneal (i.p.) administration of nicotinamide (110 mg/kg) and streptozotocin (55 mg/kg). After confirmation of T2DM on day 3, diabetic rats received monotherapies with ALA (60 mg/kg; n = 7), gliclazide (15 mg/kg; n = 7), ramipril (10 mg/kg; n = 7) or combination of the three drugs (n = 7) for 6 weeks while untreated diabetic rats received distilled water and were used as diabetic control (n = 9). Rats were then sacrificed, and blood, pancreas and heart tissues were harvested for analyses using standard methods. Results: T2DM induction caused pancreatic islet destruction, hyperglycemia, weight loss, high relative heart weight, and development of DCM, which was characterized by myocardial degeneration and vacuolation, cardiac fibrosis, elevated cardiac damage markers (plasma and cardiac creatine kinase-myocardial band, brain natriuretic peptide and cardiac troponin I). Triple combination therapy of ALA, gliclazide and ramipril preserved islet structure, maintained body weight and blood glucose level, and prevented DCM development compared to diabetic control (p < 0.001). In addition, the combination therapy markedly reduced plasma levels of inflammatory markers (IL-1β, IL-6 and TNF-α), plasma and cardiac tissue malondialdehyde, triglycerides and total cholesterol while significantly increasing cardiac glutathione and superoxide dismutase activity and high-density lipoprotein-cholesterol compared to diabetic control (p < 0.001). Mechanistically, induction of T2DM upregulated cardiac expression of TGF-β1, phosphorylated Smad2 and Smad3 proteins, which were downregulated following triple combination therapy (p < 0.001). Conclusion: Triple combination therapy of ALA, gliclazide and ramipril prevented DCM development by inhibiting TGF-β1/Smad pathway. Our findings can be extrapolated to the human heart, which would provide effective additional pharmacological therapy against DCM in T2DM patients.
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Affiliation(s)
- George J Dugbartey
- Department of Pharmacology and Toxicology, School of Pharmacy, College of Health Sciences, University of Ghana, Accra, Ghana
| | - Quinsker L Wonje
- Department of Pharmacology and Toxicology, School of Pharmacy, College of Health Sciences, University of Ghana, Accra, Ghana
| | - Karl K Alornyo
- Department of Pharmacology and Toxicology, School of Pharmacy, College of Health Sciences, University of Ghana, Accra, Ghana
| | - Louis Robertson
- Department of Pharmacology and Toxicology, School of Pharmacy, College of Health Sciences, University of Ghana, Accra, Ghana
| | - Ismaila Adams
- Department of Pharmacology and Toxicology, School of Pharmacy, College of Health Sciences, University of Ghana, Accra, Ghana
| | - Vincent Boima
- Department of Medicine and Therapeutics, University of Ghana Medical School, College of Health Sciences, University of Ghana, Accra, Ghana
| | - Samuel D Mensah
- Department of Pharmacology and Toxicology, School of Pharmacy, College of Health Sciences, University of Ghana, Accra, Ghana
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31
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Du S, Shi H, Xiong L, Wang P, Shi Y. Canagliflozin mitigates ferroptosis and improves myocardial oxidative stress in mice with diabetic cardiomyopathy. Front Endocrinol (Lausanne) 2022; 13:1011669. [PMID: 36313744 PMCID: PMC9616119 DOI: 10.3389/fendo.2022.1011669] [Citation(s) in RCA: 70] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Accepted: 09/27/2022] [Indexed: 11/13/2022] Open
Abstract
Canagliflozin (Cana), an anti-diabetes drug belongs to sodium-glucose cotransporter 2 inhibitor, is gaining interest because of its extra cardiovascular benefits. Ferroptosis is a new mode of cell death, which can promote the occurrence of diabetic cardiomyopathy (DCM). Whether Cana can alleviate DCM by inhibiting ferroptosis is the focus of this study. Here, we induced DCM models in diabetic C57BL6 mice and treated with Cana. Meanwhile, in order to exclude its hypoglycemic effect, the high glucose model in H9C2 cells were established. In the in vivo study, we observed that Cana could effectively alleviate the damage of cardiac function in DCM mice, including the increasing of lactate dehydrogenase (LDH) and cardiac troponin I (cTnI), the alleviating of myocardial fiber breakage, inflammation, collagen fiber deposition and mitochondrial structural disorder. We evaluated reactive oxygen species (ROS) levels by DCFH-DA and BODIPY 581/591 C11, in vitro Cana reduced ROS and lipid ROS in H9C2 cells induced by high glucose. Meanwhile, JC-1 fluorochrome assay showed that the decreased mitochondrial membrane potential (MMP) was increased by Cana. Furthermore, the inhibitory effects of Cana on myocardial oxidative stress and ferroptosis were verified in vivo and in vitro by protein carbonyl (PCO), malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione (GSH). As a key inducer of ferroptosis, the deposition of total iron and Fe2+ can be inhibited by Cana both in vivo and in vitro. In addition, western blot results indicated that the expression of ferritin heavy-chain (FTN-H) was down-regulated, and cystine-glutamate antiporter (xCT) was up-regulated by Cana in DCM mice and cells, suggesting that Cana inhibit ferroptosis by balancing cardiac iron homeostasis and promoting the system Xc-/GSH/GPX4 axis in DCM. These findings underscore the fact that ferroptosis plays an important role in the development and progression of DCM and targeting ferroptosis may be a novel strategy for prevention and treatment. In conclusion, Cana may exert some of its cardiovascular benefits by attenuating ferroptosis.
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Affiliation(s)
- Shuqin Du
- Central Laboratory of Molecular Medicine Research Center, Jiaxing Traditional Chinese Medicine (TCM) Hospital Affiliated to Zhejiang University of Traditional Chinese Medicine, Jiaxing, China
- Jiaxing Key Laboratory of Diabetic Angiopathy Research, Jiaxing, China
- School of Pharmacy, Zhejiang University of Technology, Hangzhou, China
- School of Medicine, Jiaxing University, Jiaxing, China
| | - Hanqiang Shi
- Central Laboratory of Molecular Medicine Research Center, Jiaxing Traditional Chinese Medicine (TCM) Hospital Affiliated to Zhejiang University of Traditional Chinese Medicine, Jiaxing, China
- Jiaxing Key Laboratory of Diabetic Angiopathy Research, Jiaxing, China
| | - Lie Xiong
- Central Laboratory of Molecular Medicine Research Center, Jiaxing Traditional Chinese Medicine (TCM) Hospital Affiliated to Zhejiang University of Traditional Chinese Medicine, Jiaxing, China
- Jiaxing Key Laboratory of Diabetic Angiopathy Research, Jiaxing, China
| | - Ping Wang
- School of Pharmacy, Zhejiang University of Technology, Hangzhou, China
| | - Yanbo Shi
- Central Laboratory of Molecular Medicine Research Center, Jiaxing Traditional Chinese Medicine (TCM) Hospital Affiliated to Zhejiang University of Traditional Chinese Medicine, Jiaxing, China
- Jiaxing Key Laboratory of Diabetic Angiopathy Research, Jiaxing, China
- *Correspondence: Yanbo Shi,
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32
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Sukumaran V, Gurusamy N, Yalcin HC, Venkatesh S. Understanding diabetes-induced cardiomyopathy from the perspective of renin angiotensin aldosterone system. Pflugers Arch 2021; 474:63-81. [PMID: 34967935 DOI: 10.1007/s00424-021-02651-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 12/02/2021] [Accepted: 12/03/2021] [Indexed: 12/31/2022]
Abstract
Experimental and clinical evidence suggests that diabetic subjects are predisposed to a distinct cardiovascular dysfunction, known as diabetic cardiomyopathy (DCM), which could be an autonomous disease independent of concomitant micro and macrovascular disorders. DCM is one of the prominent causes of global morbidity and mortality and is on a rising trend with the increase in the prevalence of diabetes mellitus (DM). DCM is characterized by an early left ventricle diastolic dysfunction associated with the slow progression of cardiomyocyte hypertrophy leading to heart failure, which still has no effective therapy. Although the well-known "Renin Angiotensin Aldosterone System (RAAS)" inhibition is considered a gold-standard treatment in heart failure, its role in DCM is still unclear. At the cellular level of DCM, RAAS induces various secondary mechanisms, adding complications to poor prognosis and treatment of DCM. This review highlights the importance of RAAS signaling and its major secondary mechanisms involving inflammation, oxidative stress, mitochondrial dysfunction, and autophagy, their role in establishing DCM. In addition, studies lacking in the specific area of DCM are also highlighted. Therefore, understanding the complex role of RAAS in DCM may lead to the identification of better prognosis and therapeutic strategies in treating DCM.
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Affiliation(s)
| | - Narasimman Gurusamy
- Department of Bioscience Research, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Huseyin C Yalcin
- Biomedical Research Center, Qatar University, Al-Tarfa, 2371, Doha, Qatar
| | - Sundararajan Venkatesh
- Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers-New Jersey Medical School, Newark, NJ, USA
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33
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Tate M, Perera N, Prakoso D, Willis AM, Deo M, Oseghale O, Qian H, Donner DG, Kiriazis H, De Blasio MJ, Gregorevic P, Ritchie RH. Bone Morphogenetic Protein 7 Gene Delivery Improves Cardiac Structure and Function in a Murine Model of Diabetic Cardiomyopathy. Front Pharmacol 2021; 12:719290. [PMID: 34690762 PMCID: PMC8532155 DOI: 10.3389/fphar.2021.719290] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Accepted: 09/24/2021] [Indexed: 12/12/2022] Open
Abstract
Diabetes is a major contributor to the increasing burden of heart failure prevalence globally, at least in part due to a disease process termed diabetic cardiomyopathy. Diabetic cardiomyopathy is characterised by cardiac structural changes that are caused by chronic exposure to the diabetic milieu. These structural changes are a major cause of left ventricular (LV) wall stiffness and the development of LV dysfunction. In the current study, we investigated the therapeutic potential of a cardiac-targeted bone morphogenetic protein 7 (BMP7) gene therapy, administered once diastolic dysfunction was present, mimicking the timeframe in which clinical management of the cardiomyopathy would likely be desired. Following 18 weeks of untreated diabetes, mice were administered with a single tail-vein injection of recombinant adeno-associated viral vector (AAV), containing the BMP7 gene, or null vector. Our data demonstrated, after 8 weeks of treatment, that rAAV6-BMP7 treatment exerted beneficial effects on LV functional and structural changes. Importantly, diabetes-induced LV dysfunction was significantly attenuated by a single administration of rAAV6-BMP7. This was associated with a reduction in cardiac fibrosis, cardiomyocyte hypertrophy and cardiomyocyte apoptosis. In conclusion, BMP7 gene therapy limited pathological remodelling in the diabetic heart, conferring an improvement in cardiac function. These findings provide insight for the potential development of treatment strategies urgently needed to delay or reverse LV pathological remodelling in the diabetic heart.
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Affiliation(s)
- Mitchel Tate
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, Australia.,Heart Failure Pharmacology, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
| | - Nimna Perera
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, Australia.,Heart Failure Pharmacology, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
| | - Darnel Prakoso
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, Australia.,Heart Failure Pharmacology, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.,School of Biosciences, The University of Melbourne, Parkville, VIC, Australia
| | - Andrew M Willis
- Heart Failure Pharmacology, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
| | - Minh Deo
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, Australia.,Heart Failure Pharmacology, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
| | - Osezua Oseghale
- Heart Failure Pharmacology, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
| | - Hongwei Qian
- Centre for Muscle Research, Department of Anatomy and Physiology, The University of Melbourne, Parkville, VIC, Australia
| | - Daniel G Donner
- Preclinical Microsurgery and Imaging, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.,Department of Cardiometabolic Health, The University of Melbourne, Parkville, VIC, Australia
| | - Helen Kiriazis
- Preclinical Microsurgery and Imaging, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.,Department of Cardiometabolic Health, The University of Melbourne, Parkville, VIC, Australia
| | - Miles J De Blasio
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, Australia.,Heart Failure Pharmacology, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.,School of Biosciences, The University of Melbourne, Parkville, VIC, Australia.,Department of Pharmacology, Monash University, Clayton, VIC, Australia
| | - Paul Gregorevic
- Centre for Muscle Research, Department of Anatomy and Physiology, The University of Melbourne, Parkville, VIC, Australia.,Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.,Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia.,Department of Neurology, The University of Washington, Seattle, WA, United States
| | - Rebecca H Ritchie
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, Australia.,Heart Failure Pharmacology, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.,Department of Pharmacology, Monash University, Clayton, VIC, Australia
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34
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Parker AM, Tate M, Prakoso D, Deo M, Willis AM, Nash DM, Donner DG, Crawford S, Kiriazis H, Granata C, Coughlan MT, De Blasio MJ, Ritchie RH. Characterisation of the Myocardial Mitochondria Structural and Functional Phenotype in a Murine Model of Diabetic Cardiomyopathy. Front Physiol 2021; 12:672252. [PMID: 34539423 PMCID: PMC8442993 DOI: 10.3389/fphys.2021.672252] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 08/10/2021] [Indexed: 12/26/2022] Open
Abstract
People affected by diabetes are at an increased risk of developing heart failure than their non-diabetic counterparts, attributed in part to a distinct cardiac pathology termed diabetic cardiomyopathy. Mitochondrial dysfunction and excess reactive oxygen species (ROS) have been implicated in a range of diabetic complications and are a common feature of the diabetic heart. In this study, we sought to characterise impairments in mitochondrial structure and function in a recently described experimental mouse model of diabetic cardiomyopathy. Diabetes was induced in 6-week-old male FVB/N mice by the combination of three consecutive-daily injections of low-dose streptozotocin (STZ, each 55 mg/kg i.p.) and high-fat diet (42% fat from lipids) for 26 weeks. At study end, diabetic mice exhibited elevated blood glucose levels and impaired glucose tolerance, together with increases in both body weight gain and fat mass, replicating several aspects of human type 2 diabetes. The myocardial phenotype of diabetic mice included increased myocardial fibrosis and left ventricular (LV) diastolic dysfunction. Elevated LV superoxide levels were also evident. Diabetic mice exhibited a spectrum of LV mitochondrial changes, including decreased mitochondria area, increased levels of mitochondrial complex-III and complex-V protein abundance, and reduced complex-II oxygen consumption. In conclusion, these data suggest that the low-dose STZ-high fat experimental model replicates some of the mitochondrial changes seen in diabetes, and as such, this model may be useful to study treatments that target the mitochondria in diabetes.
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Affiliation(s)
- Alex M Parker
- Heart Failure Pharmacology, Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC, Australia.,Baker Heart & Diabetes Institute, Melbourne, VIC, Australia.,Department of Pharmacology and Therapeutics, The University of Melbourne, Melbourne, VIC, Australia
| | - Mitchel Tate
- Heart Failure Pharmacology, Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC, Australia.,Baker Heart & Diabetes Institute, Melbourne, VIC, Australia
| | - Darnel Prakoso
- Heart Failure Pharmacology, Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC, Australia.,Baker Heart & Diabetes Institute, Melbourne, VIC, Australia
| | - Minh Deo
- Heart Failure Pharmacology, Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC, Australia
| | - Andrew M Willis
- Heart Failure Pharmacology, Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC, Australia
| | - David M Nash
- Heart Failure Pharmacology, Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC, Australia
| | - Daniel G Donner
- Baker Heart & Diabetes Institute, Melbourne, VIC, Australia.,Baker Department of Cardiometabolic Health, The University of Melbourne, Melbourne, VIC, Australia
| | - Simon Crawford
- Ramaciotti Centre for Cryo-Electron Microscopy, Monash University, Melbourne, VIC, Australia
| | - Helen Kiriazis
- Baker Heart & Diabetes Institute, Melbourne, VIC, Australia.,Baker Department of Cardiometabolic Health, The University of Melbourne, Melbourne, VIC, Australia
| | - Cesare Granata
- Department of Diabetes, Monash University, Melbourne, VIC, Australia.,Institute for Health and Sport, Victoria University, Melbourne, VIC, Australia
| | | | - Miles J De Blasio
- Heart Failure Pharmacology, Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC, Australia.,Baker Heart & Diabetes Institute, Melbourne, VIC, Australia.,Department of Pharmacology, Monash University, Melbourne, VIC, Australia
| | - Rebecca H Ritchie
- Heart Failure Pharmacology, Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC, Australia.,Baker Heart & Diabetes Institute, Melbourne, VIC, Australia.,Department of Pharmacology and Therapeutics, The University of Melbourne, Melbourne, VIC, Australia.,Department of Pharmacology, Monash University, Melbourne, VIC, Australia
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35
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Tuleta I, Frangogiannis NG. Fibrosis of the diabetic heart: Clinical significance, molecular mechanisms, and therapeutic opportunities. Adv Drug Deliv Rev 2021; 176:113904. [PMID: 34331987 PMCID: PMC8444077 DOI: 10.1016/j.addr.2021.113904] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 07/19/2021] [Accepted: 07/24/2021] [Indexed: 01/02/2023]
Abstract
In patients with diabetes, myocardial fibrosis may contribute to the pathogenesis of heart failure and arrhythmogenesis, increasing ventricular stiffness and delaying conduction. Diabetic myocardial fibrosis involves effects of hyperglycemia, lipotoxicity and insulin resistance on cardiac fibroblasts, directly resulting in increased matrix secretion, and activation of paracrine signaling in cardiomyocytes, immune and vascular cells, that release fibroblast-activating mediators. Neurohumoral pathways, cytokines, growth factors, oxidative stress, advanced glycation end-products (AGEs), and matricellular proteins have been implicated in diabetic fibrosis; however, the molecular links between the metabolic perturbations and activation of a fibrogenic program remain poorly understood. Although existing therapies using glucose- and lipid-lowering agents and neurohumoral inhibition may act in part by attenuating myocardial collagen deposition, specific therapies targeting the fibrotic response are lacking. This review manuscript discusses the clinical significance, molecular mechanisms and cell biology of diabetic cardiac fibrosis and proposes therapeutic targets that may attenuate the fibrotic response, preventing heart failure progression.
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Affiliation(s)
- Izabela Tuleta
- The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx NY, USA
| | - Nikolaos G Frangogiannis
- The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx NY, USA.
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Duan JY, Lin X, Xu F, Shan SK, Guo B, Li FXZ, Wang Y, Zheng MH, Xu QS, Lei LM, Ou-Yang WL, Wu YY, Tang KX, Yuan LQ. Ferroptosis and Its Potential Role in Metabolic Diseases: A Curse or Revitalization? Front Cell Dev Biol 2021; 9:701788. [PMID: 34307381 PMCID: PMC8299754 DOI: 10.3389/fcell.2021.701788] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Accepted: 06/04/2021] [Indexed: 12/19/2022] Open
Abstract
Ferroptosis is classified as an iron-dependent form of regulated cell death (RCD) attributed to the accumulation of lipid hydroperoxides and redox imbalance. In recent years, accumulating researches have suggested that ferroptosis may play a vital role in the development of diverse metabolic diseases, for example, diabetes and its complications (e.g., diabetic nephropathy, diabetic cardiomyopathy, diabetic myocardial ischemia/reperfusion injury and atherosclerosis [AS]), metabolic bone disease and adrenal injury. However, the specific physiopathological mechanism and precise therapeutic effect is still not clear. In this review, we summarized recent advances about the development of ferroptosis, focused on its potential character as the therapeutic target in metabolic diseases, and put forward our insights on this topic, largely to offer some help to forecast further directions.
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Affiliation(s)
- Jia-Yue Duan
- National Clinical Research Center for Metabolic Disease, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, Department of Endocrinology and Metabolism, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Xiao Lin
- Department of Radiology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Feng Xu
- National Clinical Research Center for Metabolic Disease, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, Department of Endocrinology and Metabolism, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Su-Kang Shan
- National Clinical Research Center for Metabolic Disease, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, Department of Endocrinology and Metabolism, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Bei Guo
- National Clinical Research Center for Metabolic Disease, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, Department of Endocrinology and Metabolism, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Fu-Xing-Zi Li
- National Clinical Research Center for Metabolic Disease, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, Department of Endocrinology and Metabolism, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Yi Wang
- National Clinical Research Center for Metabolic Disease, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, Department of Endocrinology and Metabolism, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Ming-Hui Zheng
- National Clinical Research Center for Metabolic Disease, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, Department of Endocrinology and Metabolism, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Qiu-Shuang Xu
- National Clinical Research Center for Metabolic Disease, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, Department of Endocrinology and Metabolism, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Li-Min Lei
- National Clinical Research Center for Metabolic Disease, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, Department of Endocrinology and Metabolism, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Wen-Lu Ou-Yang
- National Clinical Research Center for Metabolic Disease, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, Department of Endocrinology and Metabolism, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Yun-Yun Wu
- National Clinical Research Center for Metabolic Disease, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, Department of Endocrinology and Metabolism, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Ke-Xin Tang
- National Clinical Research Center for Metabolic Disease, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, Department of Endocrinology and Metabolism, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Ling-Qing Yuan
- National Clinical Research Center for Metabolic Disease, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, Department of Endocrinology and Metabolism, The Second Xiangya Hospital, Central South University, Changsha, China
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The Mystery of Diabetic Cardiomyopathy: From Early Concepts and Underlying Mechanisms to Novel Therapeutic Possibilities. Int J Mol Sci 2021; 22:ijms22115973. [PMID: 34205870 PMCID: PMC8198766 DOI: 10.3390/ijms22115973] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Revised: 05/26/2021] [Accepted: 05/30/2021] [Indexed: 02/07/2023] Open
Abstract
Diabetic patients are predisposed to diabetic cardiomyopathy, a specific form of cardiomyopathy which is characterized by the development of myocardial fibrosis, cardiomyocyte hypertrophy, and apoptosis that develops independently of concomitant macrovascular and microvascular diabetic complications. Its pathophysiology is multifactorial and poorly understood and no specific therapeutic guideline has yet been established. Diabetic cardiomyopathy is a challenging diagnosis, made after excluding other potential entities, treated with different pharmacotherapeutic agents targeting various pathophysiological pathways that need yet to be unraveled. It has great clinical importance as diabetes is a disease with pandemic proportions. This review focuses on the potential mechanisms contributing to this entity, diagnostic options, as well as on potential therapeutic interventions taking in consideration their clinical feasibility and limitations in everyday practice. Besides conventional therapies, we discuss novel therapeutic possibilities that have not yet been translated into clinical practice.
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Byrne NJ, Rajasekaran NS, Abel ED, Bugger H. Therapeutic potential of targeting oxidative stress in diabetic cardiomyopathy. Free Radic Biol Med 2021; 169:317-342. [PMID: 33910093 PMCID: PMC8285002 DOI: 10.1016/j.freeradbiomed.2021.03.046] [Citation(s) in RCA: 91] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 02/24/2021] [Accepted: 03/25/2021] [Indexed: 02/07/2023]
Abstract
Even in the absence of coronary artery disease and hypertension, diabetes mellitus (DM) may increase the risk for heart failure development. This risk evolves from functional and structural alterations induced by diabetes in the heart, a cardiac entity termed diabetic cardiomyopathy (DbCM). Oxidative stress, defined as the imbalance of reactive oxygen species (ROS) has been increasingly proposed to contribute to the development of DbCM. There are several sources of ROS production including the mitochondria, NAD(P)H oxidase, xanthine oxidase, and uncoupled nitric oxide synthase. Overproduction of ROS in DbCM is thought to be counterbalanced by elevated antioxidant defense enzymes such as catalase and superoxide dismutase. Excess ROS in the cardiomyocyte results in further ROS production, mitochondrial DNA damage, lipid peroxidation, post-translational modifications of proteins and ultimately cell death and cardiac dysfunction. Furthermore, ROS modulates transcription factors responsible for expression of antioxidant enzymes. Lastly, evidence exists that several pharmacological agents may convey cardiovascular benefit by antioxidant mechanisms. As such, increasing our understanding of the pathways that lead to increased ROS production and impaired antioxidant defense may enable the development of therapeutic strategies against the progression of DbCM. Herein, we review the current knowledge about causes and consequences of ROS in DbCM, as well as the therapeutic potential and strategies of targeting oxidative stress in the diabetic heart.
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Affiliation(s)
- Nikole J Byrne
- Division of Cardiology, Medical University of Graz, Graz, Austria
| | - Namakkal S Rajasekaran
- Cardiac Aging & Redox Signaling Laboratory, Molecular and Cellular Pathology, Department of Pathology, Birmingham, AL, USA; Division of Cardiovascular Medicine, Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA; Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - E Dale Abel
- Fraternal Order of Eagles Diabetes Research Center, Division of Endocrinology and Metabolism, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, USA
| | - Heiko Bugger
- Division of Cardiology, Medical University of Graz, Graz, Austria.
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Rabanal-Ruiz Y, Llanos-González E, Alcain FJ. The Use of Coenzyme Q10 in Cardiovascular Diseases. Antioxidants (Basel) 2021; 10:antiox10050755. [PMID: 34068578 PMCID: PMC8151454 DOI: 10.3390/antiox10050755] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 05/03/2021] [Accepted: 05/04/2021] [Indexed: 02/06/2023] Open
Abstract
CoQ10 is an endogenous antioxidant produced in all cells that plays an essential role in energy metabolism and antioxidant protection. CoQ10 distribution is not uniform among different organs, and the highest concentration is observed in the heart, though its levels decrease with age. Advanced age is the major risk factor for cardiovascular disease and endothelial dysfunction triggered by oxidative stress that impairs mitochondrial bioenergetic and reduces NO bioavailability, thus affecting vasodilatation. The rationale of the use of CoQ10 in cardiovascular diseases is that the loss of contractile function due to an energy depletion status in the mitochondria and reduced levels of NO for vasodilatation has been associated with low endogenous CoQ10 levels. Clinical evidence shows that CoQ10 supplementation for prolonged periods is safe, well-tolerated and significantly increases the concentration of CoQ10 in plasma up to 3–5 µg/mL. CoQ10 supplementation reduces oxidative stress and mortality from cardiovascular causes and improves clinical outcome in patients undergoing coronary artery bypass graft surgery, prevents the accumulation of oxLDL in arteries, decreases vascular stiffness and hypertension, improves endothelial dysfunction by reducing the source of ROS in the vascular system and increases the NO levels for vasodilation.
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Affiliation(s)
- Yoana Rabanal-Ruiz
- Department of Medical Sciences, Faculty of Medicine, University of Castilla-La Mancha, 13071 Ciudad Real, Spain; (Y.R.-R.); (E.L.-G.)
- Oxidative Stress and Neurodegeneration Group, Regional Centre for Biomedical Research CRIB, University of Castilla-La Mancha, 13071 Ciudad Real, Spain
| | - Emilio Llanos-González
- Department of Medical Sciences, Faculty of Medicine, University of Castilla-La Mancha, 13071 Ciudad Real, Spain; (Y.R.-R.); (E.L.-G.)
- Oxidative Stress and Neurodegeneration Group, Regional Centre for Biomedical Research CRIB, University of Castilla-La Mancha, 13071 Ciudad Real, Spain
| | - Francisco Javier Alcain
- Department of Medical Sciences, Faculty of Medicine, University of Castilla-La Mancha, 13071 Ciudad Real, Spain; (Y.R.-R.); (E.L.-G.)
- Oxidative Stress and Neurodegeneration Group, Regional Centre for Biomedical Research CRIB, University of Castilla-La Mancha, 13071 Ciudad Real, Spain
- Correspondence:
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Luo XM, Yan C, Feng YM. Nanomedicine for the treatment of diabetes-associated cardiovascular diseases and fibrosis. Adv Drug Deliv Rev 2021; 172:234-248. [PMID: 33417981 DOI: 10.1016/j.addr.2021.01.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Revised: 12/25/2020] [Accepted: 01/01/2021] [Indexed: 02/08/2023]
Abstract
Cardiomyopathy and fibrosis are the main causes of heart failure in diabetes patients. For therapeutic purposes, a delivery system is required to enhance antidiabetic drug efficacy and specifically target profibrotic pathways in cardiomyocytes. Nanoparticles (NPs) have distinct advantages, including biocompatibility, bioavailability, targeting efficiency, and minimal toxicity, which make them ideal for antidiabetic treatment. In this review, we overview the latest information on the pathogenesis of cardiomyopathy and fibrosis in diabetes patients. We summarize how NP applications improve insulin and liraglutide efficacy and their sustained release upon oral administration. We provide a comprehensive review of the results of NP clinical trials in diabetes patients and of animal studies investigating the effects of NP-mediated anti-fibrotic treatments. Collectively, the application of advanced NP delivery systems in the treatment of cardiomyopathy and fibrosis in diabetes patients is a promising and innovative therapeutic strategy.
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Li N, Jiang W, Wang W, Xiong R, Wu X, Geng Q. Ferroptosis and its emerging roles in cardiovascular diseases. Pharmacol Res 2021; 166:105466. [PMID: 33548489 DOI: 10.1016/j.phrs.2021.105466] [Citation(s) in RCA: 163] [Impact Index Per Article: 40.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 12/29/2020] [Accepted: 01/22/2021] [Indexed: 12/14/2022]
Abstract
Ferroptosis is a new form of regulated cell death (RCD) driven by iron-dependent lipid peroxidation, which is morphologically and mechanistically distinct from other forms of RCD including apoptosis, autophagic cell death, pyroptosis and necroptosis. Recently, ferroptosis has been found to participate in the development of various cardiovascular diseases (CVDs) including doxorubicin-induced cardiotoxicity, ischemia/reperfusion-induced cardiomyopathy, heart failure, aortic dissection and stroke. Cardiovascular homeostasis is indulged in delicate equilibrium of assorted cell types composing the heart or vessels, and how ferroptosis contributes to the pathophysiological responses in CVD progression is unclear. Herein, we reviewed recent discoveries on the basis of ferroptosis and its involvement in CVD pathogenesis, together with related therapeutic potentials, aiming to provide insights on fundamental mechanisms of ferroptosis and implications in CVDs and associated disorders.
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Affiliation(s)
- Ning Li
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China; Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Wenyang Jiang
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China; Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Wei Wang
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China; Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Rui Xiong
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China; Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Xiaojing Wu
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China; Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China.
| | - Qing Geng
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China.
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Wang L, Cai Y, Jian L, Cheung CW, Zhang L, Xia Z. Impact of peroxisome proliferator-activated receptor-α on diabetic cardiomyopathy. Cardiovasc Diabetol 2021; 20:2. [PMID: 33397369 PMCID: PMC7783984 DOI: 10.1186/s12933-020-01188-0] [Citation(s) in RCA: 80] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Accepted: 12/02/2020] [Indexed: 12/21/2022] Open
Abstract
The prevalence of cardiomyopathy is higher in diabetic patients than those without diabetes. Diabetic cardiomyopathy (DCM) is defined as a clinical condition of abnormal myocardial structure and performance in diabetic patients without other cardiac risk factors, such as coronary artery disease, hypertension, and significant valvular disease. Multiple molecular events contribute to the development of DCM, which include the alterations in energy metabolism (fatty acid, glucose, ketone and branched chain amino acids) and the abnormalities of subcellular components in the heart, such as impaired insulin signaling, increased oxidative stress, calcium mishandling and inflammation. There are no specific drugs in treating DCM despite of decades of basic and clinical investigations. This is, in part, due to the lack of our understanding as to how heart failure initiates and develops, especially in diabetic patients without an underlying ischemic cause. Some of the traditional anti-diabetic or lipid-lowering agents aimed at shifting the balance of cardiac metabolism from utilizing fat to glucose have been shown inadequately targeting multiple aspects of the conditions. Peroxisome proliferator-activated receptor α (PPARα), a transcription factor, plays an important role in mediating DCM-related molecular events. Pharmacological targeting of PPARα activation has been demonstrated to be one of the important strategies for patients with diabetes, metabolic syndrome, and atherosclerotic cardiovascular diseases. The aim of this review is to provide a contemporary view of PPARα in association with the underlying pathophysiological changes in DCM. We discuss the PPARα-related drugs in clinical applications and facts related to the drugs that may be considered as risky (such as fenofibrate, bezafibrate, clofibrate) or safe (pemafibrate, metformin and glucagon-like peptide 1-receptor agonists) or having the potential (sodium-glucose co-transporter 2 inhibitor) in treating DCM.
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Affiliation(s)
- Lin Wang
- Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
- Department of Anaesthesiology, The University of Hong Kong, Hong Kong, SAR, China
| | - Yin Cai
- Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
- Department of Anaesthesiology, The University of Hong Kong, Hong Kong, SAR, China
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong, SAR, China
| | - Liguo Jian
- Department of Cardiology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Chi Wai Cheung
- Department of Anaesthesiology, The University of Hong Kong, Hong Kong, SAR, China
| | - Liangqing Zhang
- Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China.
| | - Zhengyuan Xia
- Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China.
- Department of Anaesthesiology, The University of Hong Kong, Hong Kong, SAR, China.
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43
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Tan YY, Chen LX, Fang L, Zhang Q. Cardioprotective effects of polydatin against myocardial injury in diabetic rats via inhibition of NADPH oxidase and NF-κB activities. BMC Complement Med Ther 2020; 20:378. [PMID: 33308195 PMCID: PMC7733248 DOI: 10.1186/s12906-020-03177-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Accepted: 12/06/2020] [Indexed: 02/06/2023] Open
Abstract
Background Diabetic cardiomyopathy is a main cause of the increased morbidity in diabetic patients, no effective treatment is available so far. Polydatin, a resveratrol glucoside isolated from the Polygonum cuspidatum, was found by our and others have antioxidant and cardioprotective activities. Therapeutic effects of polydatin on diabetic cardiomyopathy and the possible mechanisms remains unclear. This study aimed to investigate the cardioprotective effects and underlying mechanisms of polydatin on myocardial injury induced by hyperglycemia. Methods Diabetes in rats was made by high-fat diet combined with multiple low doses of streptozotocin, and then treated with polydatin (100 mg·kg-1·day-1, by gavage) for 8 weeks. Cardiac function was examined by echocardiography. Myocardial tissue and blood samples were collected for histology, protein and metabolic characteristics analysis. In cultured H9c2 cells with 30 mM of glucose, the direct effects of polydatin on myocyte injury were also observed. Results In diabetic rats, polydatin administration significantly improved myocardial dysfunction and attenuated histological abnormalities, as evidenced by elevating left ventricular shortening fraction and ejection fraction, as well as reducing cardiac hypertrophy and interstitial fibrosis. In cultured H9c2 cells, pretreatment of polydatin dose-dependently inhibited high glucose-induced cardiomyocyte injury. Further observation evidenced that polydatin suppressed the increase in the reactive oxygen species levels, NADPH oxidase activity and inflammatory cytokines production induced by hyperglycemia in vivo and in vitro. Polydatin also prevented the increase expression of NOX4, NOX2 and NF-κB in the high glucose -stimulated H9c2 cells and diabetic hearts. Conclusions Our results demonstrate that the cardioprotective effect of polydatin against hyperglycemia-induced myocardial injury is mediated by inhibition of NADPH oxidase and NF-κB activity. The findings may provide a novel understanding the mechanisms of the polydatin to be a potential treatment of diabetic cardiomyopathy. Supplementary Information The online version contains supplementary material available at 10.1186/s12906-020-03177-y.
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Affiliation(s)
- Ying-Ying Tan
- Shaanxi Key Laboratory of Chinese Medicine Encephalopathy, Shaanxi University of Chinese Medicine, Century Avenue, Xianyang, Shaanxi, 712046, P. R. China.,Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, 712046, P. R. China
| | - Lei-Xin Chen
- Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, 712046, P. R. China
| | - Ling Fang
- Shaanxi Key Laboratory of Chinese Medicine Encephalopathy, Shaanxi University of Chinese Medicine, Century Avenue, Xianyang, Shaanxi, 712046, P. R. China
| | - Qi Zhang
- Shaanxi Key Laboratory of Chinese Medicine Encephalopathy, Shaanxi University of Chinese Medicine, Century Avenue, Xianyang, Shaanxi, 712046, P. R. China.
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Gu X, Shi Y, Chen X, Sun Z, Luo W, Hu X, Jin G, You S, Qian Y, Wu W, Liang G, Wu G, Chen Z, Chen X. Isoliquiritigenin attenuates diabetic cardiomyopathy via inhibition of hyperglycemia-induced inflammatory response and oxidative stress. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2020; 78:153319. [PMID: 32950951 DOI: 10.1016/j.phymed.2020.153319] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 08/28/2020] [Accepted: 08/31/2020] [Indexed: 06/11/2023]
Abstract
BACKGROUND Inflammation and oxidative stress play essential roles in the occurrence and progression of diabetic cardiomyopathy (DCM). Isoliquiritigenin (ISL), a natural chalcone, exhibits strong anti-inflammatory and antioxidant activities. HYPOTHESIS/PURPOSE In this study, we aimed to investigate the protective effects of ISL on DCM using high glucose (HG)-challenged cultured cardiomyocytes and streptozotocin (STZ)-induced diabetic mice. STUDY DESIGN AND METHODS Embryonic rat heart-derived H9c2 cells challenged with a high concentration of glucose were used to evaluate the anti-inflammatory and antioxidant effects of ISL. STZ-induced diabetic mice were used to study the effects of ISL in DCM in vivo. Furthermore, cardiac fibrosis, hypertrophy, and apoptosis were explored both in vitro and in vivo. RESULTS ISL effectively inhibited HG-induced hypertrophy, fibrosis, and apoptosis probably by alleviating the inflammatory response and oxidative stress in H9c2 cells. Results from in vivo experiments showed that ISL exhibited anti-inflammatory and antioxidant stress activities that were characterized by the attenuation of cardiac hypertrophy, fibrosis, and apoptosis, which resulted in the maintenance of cardiac function. The protective effects of ISL against inflammation and oxidative stress were mediated by the inhibition of mitogen-activated protein kinases (MAPKs) and induction of nuclear factor-erythroid 2 related factor 2 (Nrf2) signaling pathway, respectively. CONCLUSION Our results provided compelling evidence that ISL, by virtue of neutralizing excessive inflammatory response and oxidative stress, could be a promising agent in the treatment of DCM. Targeting the MAPKs and Nrf2 signaling pathway might be an effective therapeutic strategy for the prevention and treatment of DCM.
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Affiliation(s)
- Xuemei Gu
- Department of Endocrinology, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yujuan Shi
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China; Department of Endocrinology, Jiangshan People's Hospital, Jiangshan, Zhejiang, China
| | - Xiaojun Chen
- Department of Endocrinology, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Zijia Sun
- Department of Rehabilitation, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Wu Luo
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xiang Hu
- Department of Endocrinology, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Ge Jin
- Department of Cardiology, the Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Shengban You
- Department of Cardiology, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yuanyuan Qian
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Wenjun Wu
- Department of Endocrinology, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Guang Liang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Gaojun Wu
- Department of Cardiology, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
| | - Zimiao Chen
- Department of Endocrinology, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
| | - Xiong Chen
- Department of Endocrinology, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China; Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
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Khan S, Ahmad SS, Kamal MA. Diabetic Cardiomyopathy: From Mechanism to Management in a Nutshell. Endocr Metab Immune Disord Drug Targets 2020; 21:268-281. [PMID: 32735531 DOI: 10.2174/1871530320666200731174724] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2019] [Revised: 06/03/2020] [Accepted: 07/06/2020] [Indexed: 11/22/2022]
Abstract
Diabetic cardiomyopathy (DCM) is a significant complication of diabetes mellitus characterized by gradually failing heart with detrimental cardiac remodelings, such as fibrosis and diastolic and systolic dysfunction, which is not directly attributable to coronary artery disease. Insulin resistance and resulting hyperglycemia is the main trigger involved in the initiation of diabetic cardiomyopathy. There is a constellation of many pathophysiological events, such as lipotoxicity, oxidative stress, inflammation, inappropriate activation of the renin-angiotensin-aldosterone system, dysfunctional immune modulation promoting increased rate of cardiac cell injury, apoptosis, and necrosis, which ultimately culminates into interstitial fibrosis, cardiac stiffness, diastolic dysfunction, initially, and later systolic dysfunction too. These events finally lead to clinical heart failure of DCM. Herein, The pathophysiology of DCM is briefly discussed. Furthermore, potential therapeutic strategies currently used for DCM are also briefly mentioned.
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Affiliation(s)
- Shahzad Khan
- Department of Pathophysiology, Wuhan University School of Medicine, Hubei, Wuhan, China
| | - Syed S Ahmad
- Department of Bioengineering, Faculty of Engineering, Integral University, Lucknow, India
| | - Mohammad A Kamal
- King Fahd Medical Research Center, King Abdulaziz University, P.O. Box 80216, Jeddah 21589, Saudi Arabia
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Waldman M, Arad M, Abraham NG, Hochhauser E. The Peroxisome Proliferator-Activated Receptor-Gamma Coactivator-1α-Heme Oxygenase 1 Axis, a Powerful Antioxidative Pathway with Potential to Attenuate Diabetic Cardiomyopathy. Antioxid Redox Signal 2020; 32:1273-1290. [PMID: 32027164 PMCID: PMC7232636 DOI: 10.1089/ars.2019.7989] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Accepted: 12/18/2019] [Indexed: 02/07/2023]
Abstract
Significance: From studies of diabetic animal models, the downregulation of peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α)-heme oxygenase 1 (HO-1) axis appears to be a crucial event in the development of obesity and diabetic cardiomyopathy (DCM). In this review, we discuss the role of metabolic and biochemical stressors in the rodent and human pathophysiology of DCM. A crucial contributor for many cardiac pathologies is excessive production of reactive oxygen species (ROS) pathologies, which lead to extensive cellular damage by impairing mitochondrial function and directly oxidizing DNA, proteins, and lipid membranes. We discuss the role of ROS production and inflammatory pathways with multiple contributing and confounding factors leading to DCM. Recent Advances: The relevant biochemical pathways that are critical to a therapeutic approach to treat DCM, specifically caloric restriction and its relation to the PGC-1α-HO-1 axis in the attenuation of DCM, are elucidated. Critical Issues: The increased prevalence of diabetes mellitus type 2, a major contributor to unique cardiomyopathy characterized by cardiomyocyte hypertrophy with no effective clinical treatment. This review highlights the role of mitochondrial dysfunction in the development of DCM and potential oxidative targets to attenuate oxidative stress and attenuate DCM. Future Directions: Targeting the PGC-1α-HO-1 axis is a promising approach to ameliorate DCM through improvement in mitochondrial function and antioxidant defenses. A pharmacological inducer to activate PGC-1α and HO-1 described in this review may be a promising therapeutic approach in the clinical setting.
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Affiliation(s)
- Maayan Waldman
- Cardiac Research Laboratory, Felsenstein Medical Research Institute at Rabin Medical Center, Tel Aviv University, Tel Aviv, Israel
- Cardiac Leviev Heart Center, Sheba Medical Center, Tel Hashomer, Sackler School of Medicine, Tel Aviv University, Ramat Gan, Israel
| | - Michael Arad
- Cardiac Leviev Heart Center, Sheba Medical Center, Tel Hashomer, Sackler School of Medicine, Tel Aviv University, Ramat Gan, Israel
| | - Nader G. Abraham
- Department of Pharmacology, New York Medical College, Valhalla, New York, USA
| | - Edith Hochhauser
- Cardiac Research Laboratory, Felsenstein Medical Research Institute at Rabin Medical Center, Tel Aviv University, Tel Aviv, Israel
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Han X, Liu P, Liu M, Wei Z, Fan S, Wang X, Sun S, Chu L. [6]-Gingerol Ameliorates ISO-Induced Myocardial Fibrosis by Reducing Oxidative Stress, Inflammation, and Apoptosis through Inhibition of TLR4/MAPKs/NF-κB Pathway. Mol Nutr Food Res 2020; 64:e2000003. [PMID: 32438504 DOI: 10.1002/mnfr.202000003] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2020] [Revised: 04/30/2020] [Indexed: 12/15/2022]
Abstract
SCOPE [6]-Gingerol is one of the primary pungent constituents of ginger. While [6]-gingerol has many pharmacological effects, its benefits for myocardial fibrosis, including its exact role and underlying mechanisms, remain largely unexplored. The present study is designed to characterize the cardio-protective effects of [6]-gingerol in myocardial fibrosis mice and possible underlying mechanisms. METHODS AND RESULTS Mice are subcutaneously injected with isoproterenol (ISO, 10 mg kg-1 ) and gavaged with [6]-gingerol (10, 20 mg kg-1 day-1 ) for 14 days. Pathological alterations, fibrosis, oxidative stress, inflammation response, and apoptosis are examined. In ISO-induced myocardial fibrosis, [6]-gingerol treatment decreases the J-point, heart rate, cardiac weight index, left ventricle weight index, creatine kinase (CK), and lactate dehydrogenase serum levels, calcium concentration, reactive oxygen species, malondialdehyde, and glutathione disulfide (GSSG), and increases levels of superoxide dismutase, catalase, glutathione, and GSH/GSSG. Further, [6]-gingerol improved ISO-induced morphological pathologies, inhibited inflammation and apoptosis, and suppressed the toll-like receptor-4 (TLR4)/mitogen-activated protein kinases (MAPKs)/nuclear factor κB (NF-κB) signaling pathways. CONCLUSION The protective effect of [6]-gingerol in mice with ISO-induced myocardial fibrosis may be related to the inhibition of oxidative stress, inflammation, and apoptosis, potentially through the TLR4/MAPKs/NF-κB signaling pathway.
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Affiliation(s)
- Xue Han
- School of Pharmacy, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, 050200, China.,Hebei Higher Education Institute Applied Technology Research Center on TCM Formula Preparation, Shijiazhuang, Hebei, 050091, China
| | - Panpan Liu
- School of Pharmacy, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, 050200, China
| | - Miaomiao Liu
- School of Pharmacy, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, 050200, China
| | - Ziheng Wei
- School of Pharmacy, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, 050200, China
| | - Sen Fan
- School of Mechanical Engineering, Hebei University of Science and Technology, Shijiazhuang, Hebei, 050018, China
| | - Xiangting Wang
- Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Shijiazhuang, Hebei, 050200, China.,School of Integrative Medicine, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, 050200, China
| | - Shijiang Sun
- Affiliated Hospital, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, 050200, China
| | - Li Chu
- School of Pharmacy, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, 050200, China.,Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Shijiazhuang, Hebei, 050200, China
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Abstract
Diabetes mellitus predisposes affected individuals to a significant spectrum of cardiovascular complications, one of the most debilitating in terms of prognosis is heart failure. Indeed, the increasing global prevalence of diabetes mellitus and an aging population has given rise to an epidemic of diabetes mellitus-induced heart failure. Despite the significant research attention this phenomenon, termed diabetic cardiomyopathy, has received over several decades, understanding of the full spectrum of potential contributing mechanisms, and their relative contribution to this heart failure phenotype in the specific context of diabetes mellitus, has not yet been fully resolved. Key recent preclinical discoveries that comprise the current state-of-the-art understanding of the basic mechanisms of the complex phenotype, that is, the diabetic heart, form the basis of this review. Abnormalities in each of cardiac metabolism, physiological and pathophysiological signaling, and the mitochondrial compartment, in addition to oxidative stress, inflammation, myocardial cell death pathways, and neurohumoral mechanisms, are addressed. Further, the interactions between each of these contributing mechanisms and how they align to the functional, morphological, and structural impairments that characterize the diabetic heart are considered in light of the clinical context: from the disease burden, its current management in the clinic, and where the knowledge gaps remain. The need for continued interrogation of these mechanisms (both known and those yet to be identified) is essential to not only decipher the how and why of diabetes mellitus-induced heart failure but also to facilitate improved inroads into the clinical management of this pervasive clinical challenge.
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Affiliation(s)
- Rebecca H. Ritchie
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville campus), Parkville, Victoria 3052, Australia
| | - E. Dale Abel
- Division of Endocrinology and Metabolism, University of Iowa Carver College of Medicine, Iowa City, IA 52242, United States
- Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, United States
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Arad M, Waldman M, Abraham NG, Hochhauser E. Therapeutic approaches to diabetic cardiomyopathy: Targeting the antioxidant pathway. Prostaglandins Other Lipid Mediat 2020; 150:106454. [PMID: 32413571 DOI: 10.1016/j.prostaglandins.2020.106454] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Revised: 03/23/2020] [Accepted: 05/06/2020] [Indexed: 12/25/2022]
Abstract
The global epidemic of cardiovascular disease continues unabated and remains the leading cause of death both in the US and worldwide. We hereby summarize the available therapies for diabetes and cardiovascular disease in diabetics. Clearly, the current approaches to diabetic heart disease often target the manifestations and certain mediators but not the specific pathways leading to myocardial injury, remodeling and dysfunction. Better understanding of the molecular events determining the evolution of diabetic cardiomyopathy will provide insight into the development of specific and targeted therapies. Recent studies largely increased our understanding of the role of enhanced inflammatory response, ROS production, as well as the contribution of Cyp-P450-epoxygenase-derived epoxyeicosatrienoic acid (EET), Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1α (PGC-1α), Heme Oxygenase (HO)-1 and 20-HETE in pathophysiology and therapy of cardiovascular disease. PGC-1α increases production of the HO-1 which has a major role in protecting the heart against oxidative stress, microcirculation and mitochondrial dysfunction. This review describes the potential drugs and their downstream targets, PGC-1α and HO-1, as major loci for developing therapeutic approaches beside diet and lifestyle modification for the treatment and prevention of heart disease associated with obesity and diabetes.
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Affiliation(s)
- Michael Arad
- Leviev Heart Center, Sheba Medical Center, Tel Hashomer, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
| | - Maayan Waldman
- Leviev Heart Center, Sheba Medical Center, Tel Hashomer, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; Cardiac Research Laboratory, Felsenstein Medical Research Institute, Tel Aviv University, Tel Aviv, Israel
| | - Nader G Abraham
- Department of Pharmacology, New York Medical College, Valhalla, NY 10595, USA
| | - Edith Hochhauser
- Cardiac Research Laboratory, Felsenstein Medical Research Institute, Tel Aviv University, Tel Aviv, Israel.
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Qi B, He L, Zhao Y, Zhang L, He Y, Li J, Li C, Zhang B, Huang Q, Xing J, Li F, Li Y, Ji L. Akap1 deficiency exacerbates diabetic cardiomyopathy in mice by NDUFS1-mediated mitochondrial dysfunction and apoptosis. Diabetologia 2020; 63:1072-1087. [PMID: 32072193 DOI: 10.1007/s00125-020-05103-w] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Accepted: 01/06/2020] [Indexed: 12/22/2022]
Abstract
AIMS/HYPOTHESIS Diabetic cardiomyopathy, characterised by increased oxidative damage and mitochondrial dysfunction, contributes to the increased risk of heart failure in individuals with diabetes. Considering that A-kinase anchoring protein 121 (AKAP1) is localised in the mitochondrial outer membrane and plays key roles in the regulation of mitochondrial function, this study aimed to investigate the role of AKAP1 in diabetic cardiomyopathy and explore its underlying mechanisms. METHODS Loss- and gain-of-function approaches were used to investigate the role of AKAP1 in diabetic cardiomyopathy. Streptozotocin (STZ) was injected into Akap1-knockout (Akap1-KO) mice and their wild-type (WT) littermates to induce diabetes. In addition, primary neonatal cardiomyocytes treated with high glucose were used as a cell model of diabetes. Cardiac function was assessed with echocardiography. Akap1 overexpression was conducted by injecting adeno-associated virus 9 carrying Akap1 (AAV9-Akap1). LC-MS/MS analysis and functional experiments were used to explore underlying molecular mechanisms. RESULTS AKAP1 was downregulated in the hearts of STZ-induced diabetic mouse models. Akap1-KO significantly aggravated cardiac dysfunction in the STZ-treated diabetic mice when compared with WT diabetic littermates, as evidenced by the left ventricular ejection fraction (LVEF; STZ-treated WT mice [WT/STZ] vs STZ-treated Akap1-KO mice [KO/STZ], 51.6% vs 41.6%). Mechanistically, Akap1 deficiency impaired mitochondrial respiratory function characterised by reduced ATP production. Additionally, Akap1 deficiency increased cardiomyocyte apoptosis via enhanced mitochondrial reactive oxygen species (ROS) production. Furthermore, immunoprecipitation and mass spectrometry analysis indicated that AKAP1 interacted with the NADH-ubiquinone oxidoreductase 75 kDa subunit (NDUFS1). Specifically, Akap1 deficiency inhibited complex I activity by preventing translocation of NDUFS1 from the cytosol to mitochondria. Akap1 deficiency was also related to decreased ATP production and enhanced mitochondrial ROS-related apoptosis. In contrast, restoration of AKAP1 expression in the hearts of STZ-treated diabetic mice promoted translocation of NDUFS1 to mitochondria and alleviated diabetic cardiomyopathy in the LVEF (WT/STZ injected with adeno-associated virus carrying gfp [AAV9-gfp] vs WT/STZ AAV9-Akap1, 52.4% vs 59.6%; KO/STZ AAV9-gfp vs KO/STZ AAV9-Akap1, 42.2% vs 57.6%). CONCLUSIONS/INTERPRETATION Our study provides the first evidence that Akap1 deficiency exacerbates diabetic cardiomyopathy by impeding mitochondrial translocation of NDUFS1 to induce mitochondrial dysfunction and cardiomyocyte apoptosis. Our findings suggest that Akap1 upregulation has therapeutic potential for myocardial injury in individuals with diabetes.
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Affiliation(s)
- Bingchao Qi
- Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, 1 Xinsi Road, Xi'an, 710038, China
| | - Linjie He
- State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, China
- Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi'an, China
| | - Ya Zhao
- State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, China
- Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi'an, China
- Laboratory Animal Center, Fourth Military Medical University, Xi'an, China
| | - Ling Zhang
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, 169 Changle West Road, Xi'an, 710032, China
| | - Yuanfang He
- State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, China
- Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi'an, China
| | - Jun Li
- State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, China
- Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi'an, China
| | - Congye Li
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, 169 Changle West Road, Xi'an, 710032, China
| | - Bo Zhang
- State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, China
- Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi'an, China
| | - Qichao Huang
- State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, China
- Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi'an, China
| | - Jinliang Xing
- State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, China
- Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi'an, China
| | - Fei Li
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, 169 Changle West Road, Xi'an, 710032, China.
| | - Yan Li
- Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, 1 Xinsi Road, Xi'an, 710038, China.
| | - Lele Ji
- Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, 169 Changle West Road, Xi'an, 710032, China.
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