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1
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Juricic S, Klac J, Stojkovic S, Tesic M, Jovanovic I, Aleksandric S, Dobric M, Zivkovic S, Maricic B, Simeunovic D, Lasica R, Dikic M, Banovic M, Beleslin B. Molecular and Pathophysiological Mechanisms Leading to Ischemic Heart Disease in Patients with Diabetes Mellitus. Int J Mol Sci 2025; 26:3924. [PMID: 40362167 PMCID: PMC12071796 DOI: 10.3390/ijms26093924] [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] [Subscribe] [Scholar Register] [Received: 02/17/2025] [Revised: 04/07/2025] [Accepted: 04/10/2025] [Indexed: 05/15/2025] Open
Abstract
Coronary atherosclerosis in patients with diabetes mellitus is the most significant pathophysiological mechanism responsible for ischemic heart disease. Atherosclerosis in diabetes is premature, more diffuse, and more progressive, and it affects more coronary blood vessels compared to non-diabetics. Atherosclerosis begins with endothelial dysfunction, continues with the formation of fatty streaks in the intima of coronary arteries, and ends with the appearance of an atherosclerotic plaque that expands centrifugally and remodels the coronary artery. If the atherosclerotic plaque is injured, a thrombus forms at the site of the damage, which can lead to vessel occlusion and potentially fatal consequences. Diabetes mellitus and atherosclerosis are connected through several pathological pathways. Among the most significant factors that lead to atherosclerosis in diabetics are hyperglycemia, insulin resistance, oxidative stress, dyslipidemia, and chronic inflammation. Chronic inflammation is currently considered one of the most important factors in the development of atherosclerosis. However, to date, no adequate anti-inflammatory therapeutic measures have been found to prevent the progression of the atherosclerotic process, and they remain a subject of ongoing research. In this review, we summarize the most significant pathophysiological mechanisms that link atherosclerosis and diabetes mellitus.
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Affiliation(s)
- Stefan Juricic
- Clinic for Cardiology, University Clinical Center of Serbia, 11000 Belgrade, Serbia; (S.S.); (M.T.); (I.J.); (S.A.); (D.S.); (M.D.); (M.B.)
| | - Jovana Klac
- Department of Cardiology, Emergency Center, University Clinical Center of Serbia, 11000 Belgrade, Serbia; (J.K.); (R.L.)
| | - Sinisa Stojkovic
- Clinic for Cardiology, University Clinical Center of Serbia, 11000 Belgrade, Serbia; (S.S.); (M.T.); (I.J.); (S.A.); (D.S.); (M.D.); (M.B.)
- School of Medicine, University of Belgrade, 11000 Belgrade, Serbia;
| | - Milorad Tesic
- Clinic for Cardiology, University Clinical Center of Serbia, 11000 Belgrade, Serbia; (S.S.); (M.T.); (I.J.); (S.A.); (D.S.); (M.D.); (M.B.)
- School of Medicine, University of Belgrade, 11000 Belgrade, Serbia;
| | - Ivana Jovanovic
- Clinic for Cardiology, University Clinical Center of Serbia, 11000 Belgrade, Serbia; (S.S.); (M.T.); (I.J.); (S.A.); (D.S.); (M.D.); (M.B.)
| | - Srdjan Aleksandric
- Clinic for Cardiology, University Clinical Center of Serbia, 11000 Belgrade, Serbia; (S.S.); (M.T.); (I.J.); (S.A.); (D.S.); (M.D.); (M.B.)
- School of Medicine, University of Belgrade, 11000 Belgrade, Serbia;
| | - Milan Dobric
- School of Medicine, University of Belgrade, 11000 Belgrade, Serbia;
- Dedinje Cardiovascular Institute, 11000 Belgrade, Serbia;
| | | | - Bojan Maricic
- Clinic of Cardiology, University Clinical Center Nis, 18000 Nis, Serbia;
| | - Dejan Simeunovic
- Clinic for Cardiology, University Clinical Center of Serbia, 11000 Belgrade, Serbia; (S.S.); (M.T.); (I.J.); (S.A.); (D.S.); (M.D.); (M.B.)
- School of Medicine, University of Belgrade, 11000 Belgrade, Serbia;
| | - Ratko Lasica
- Department of Cardiology, Emergency Center, University Clinical Center of Serbia, 11000 Belgrade, Serbia; (J.K.); (R.L.)
- School of Medicine, University of Belgrade, 11000 Belgrade, Serbia;
| | - Miodrag Dikic
- Clinic for Cardiology, University Clinical Center of Serbia, 11000 Belgrade, Serbia; (S.S.); (M.T.); (I.J.); (S.A.); (D.S.); (M.D.); (M.B.)
| | - Marko Banovic
- Clinic for Cardiology, University Clinical Center of Serbia, 11000 Belgrade, Serbia; (S.S.); (M.T.); (I.J.); (S.A.); (D.S.); (M.D.); (M.B.)
- School of Medicine, University of Belgrade, 11000 Belgrade, Serbia;
| | - Branko Beleslin
- Clinic for Cardiology, University Clinical Center of Serbia, 11000 Belgrade, Serbia; (S.S.); (M.T.); (I.J.); (S.A.); (D.S.); (M.D.); (M.B.)
- School of Medicine, University of Belgrade, 11000 Belgrade, Serbia;
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Tashkandi AJ, Gorman A, McGoldrick Mathers E, Carney G, Yacoub A, Setyaningsih WAW, Kuburas R, Margariti A. Metabolic and Mitochondrial Dysregulations in Diabetic Cardiac Complications. Int J Mol Sci 2025; 26:3016. [PMID: 40243689 PMCID: PMC11988959 DOI: 10.3390/ijms26073016] [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: 02/01/2025] [Revised: 03/16/2025] [Accepted: 03/24/2025] [Indexed: 04/18/2025] Open
Abstract
The growing prevalence of diabetes highlights the urgent need to study diabetic cardiovascular complications, specifically diabetic cardiomyopathy, which is a diabetes-induced myocardial dysfunction independent of hypertension or coronary artery disease. This review examines the role of mitochondrial dysfunction in promoting diabetic cardiac dysfunction and highlights metabolic mechanisms such as hyperglycaemia-induced oxidative stress. Chronic hyperglycaemia and insulin resistance can activate harmful pathways, including advanced glycation end-products (AGEs), protein kinase C (PKC) and hexosamine signalling, uncontrolled reactive oxygen species (ROS) production and mishandling of Ca2+ transient. These processes lead to cardiomyocyte apoptosis, fibrosis and contractile dysfunction. Moreover, endoplasmic reticulum (ER) stress and dysregulated RNA-binding proteins (RBPs) and extracellular vesicles (EVs) contribute to tissue damage, which drives cardiac function towards heart failure (HF). Advanced patient-derived induced pluripotent stem cell (iPSC) cardiac organoids (iPS-COs) are transformative tools for modelling diabetic cardiomyopathy and capturing human disease's genetic, epigenetic and metabolic hallmarks. iPS-COs may facilitate the precise examination of molecular pathways and therapeutic interventions. Future research directions encourage the integration of advanced models with mechanistic techniques to promote novel therapeutic strategies.
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Affiliation(s)
| | | | | | | | | | | | - Refik Kuburas
- Wellcome Wolfson Institute of Experimental Medicine, Queens University Belfast, Belfast BT9 7BL, Northern Ireland, UK; (A.J.T.); (A.G.); (E.M.M.); (G.C.); (A.Y.); (W.A.W.S.)
| | - Andriana Margariti
- Wellcome Wolfson Institute of Experimental Medicine, Queens University Belfast, Belfast BT9 7BL, Northern Ireland, UK; (A.J.T.); (A.G.); (E.M.M.); (G.C.); (A.Y.); (W.A.W.S.)
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3
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Jaiswal A, Yadav P, Rawat PS, Kaur M, Babu SS, Khurana A, Bhatti JS, Navik U. Empagliflozin in diabetic cardiomyopathy: elucidating mechanisms, therapeutic potentials, and future directions. Mol Biol Rep 2025; 52:158. [PMID: 39853512 DOI: 10.1007/s11033-025-10260-5] [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: 11/07/2024] [Accepted: 01/13/2025] [Indexed: 01/26/2025]
Abstract
Diabetic cardiomyopathy (DCM) represents a significant health burden, exacerbated by the global increase in type 2 diabetes mellitus (T2DM). This condition contributes substantially to the morbidity and mortality associated with diabetes, primarily through myocardial dysfunction independent of coronary artery disease. Current treatment strategies focus on managing symptoms rather than targeting the underlying pathophysiological mechanisms, highlighting a critical need for specific therapeutic interventions. This review explores the multifaceted role of empagliflozin, a sodium-glucose cotransporter 2 (SGLT-2) inhibitor, in addressing the complex etiology of DCM. We discuss the key mechanisms by which hyperglycemia contributes to cardiac dysfunction, including oxidative stress, mitochondrial impairment, and inflammation, and how empagliflozin mitigates these effects. Empagliflozin's effects on reducing hospitalization for heart failure and potentially lowering cardiovascular mortality mark it as a promising candidate for DCM management. By elucidating the underlying mechanisms through which empagliflozin operates, this review underscores its therapeutic potential and paves the way for future research into its broader applications in diabetic cardiac care. This synthesis aims to foster a deeper understanding of DCM and encourage the integration of empagliflozin into treatment paradigms, offering hope for improved outcomes in patients suffering from this debilitating condition.
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Affiliation(s)
- Aiswarya Jaiswal
- Department of Pharmacology, Central University of Punjab, Bathinda, Punjab, 151401, India
| | - Poonam Yadav
- Department of Pharmacology, Central University of Punjab, Bathinda, Punjab, 151401, India
| | - Pushkar Singh Rawat
- Department of Pharmacology, Central University of Punjab, Bathinda, Punjab, 151401, India
| | - Maninder Kaur
- Department of Human Anatomy, Bhojia Dental College and Hospital, Budh, Baddi, Himachal Pradesh, 173205, India
| | | | - Amit Khurana
- Department of Pharmacology, Central University of Punjab, Bathinda, Punjab, 151401, India
| | - Jasvinder Singh Bhatti
- Laboratory of Translational Medicine and Nanotherapeutics, Department of Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda, 151401, India.
| | - Umashanker Navik
- Department of Pharmacology, Central University of Punjab, Bathinda, Punjab, 151401, India.
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4
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Giardinelli S, Meliota G, Mentino D, D’Amato G, Faienza MF. Molecular Basis of Cardiomyopathies in Type 2 Diabetes. Int J Mol Sci 2024; 25:8280. [PMID: 39125850 PMCID: PMC11313011 DOI: 10.3390/ijms25158280] [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: 06/22/2024] [Revised: 07/23/2024] [Accepted: 07/26/2024] [Indexed: 08/12/2024] Open
Abstract
Diabetic cardiomyopathy (DbCM) is a common complication in individuals with type 2 diabetes mellitus (T2DM), and its exact pathogenesis is still debated. It was hypothesized that chronic hyperglycemia and insulin resistance activate critical cellular pathways that are responsible for numerous functional and anatomical perturbations in the heart. Interstitial inflammation, oxidative stress, myocardial apoptosis, mitochondria dysfunction, defective cardiac metabolism, cardiac remodeling, hypertrophy and fibrosis with consequent impaired contractility are the most common mechanisms implicated. Epigenetic changes also have an emerging role in the regulation of these crucial pathways. The aim of this review was to highlight the increasing knowledge on the molecular mechanisms of DbCM and the new therapies targeting specific pathways.
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Affiliation(s)
- Silvia Giardinelli
- Department of Medical Sciences, Pediatrics, University of Ferrara, 44121 Ferrara, Italy;
| | - Giovanni Meliota
- Department of Pediatric Cardiology, Giovanni XXIII Pediatric Hospital, 70126 Bari, Italy;
| | - Donatella Mentino
- Pediatric Unit, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari “Aldo Moro”, 70124 Bari, Italy;
| | - Gabriele D’Amato
- Neonatal Intensive Care Unit, Di Venere Hospital, 70012 Bari, Italy;
| | - Maria Felicia Faienza
- Pediatric Unit, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari “Aldo Moro”, 70124 Bari, Italy;
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5
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Delligatti CE, Kirk JA. Glycation in the cardiomyocyte. VITAMINS AND HORMONES 2024; 125:47-88. [PMID: 38997172 PMCID: PMC11578284 DOI: 10.1016/bs.vh.2024.04.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 07/14/2024]
Abstract
Glycation is a protein post-translational modification that can occur on lysine and arginine residues as a result of a non-enzymatic process known as the Maillard reaction. This modification is irreversible, so the only way it can be removed is by protein degradation and replacement. Small reactive carbonyl species, glyoxal and methylglyoxal, are the primary glycating agents and are elevated in several conditions associated with an increased risk of cardiovascular disease, including diabetes, rheumatoid arthritis, smoking, and aging. Thus, how protein glycation impacts the cardiomyocyte is of particular interest, to both understand how these conditions increase the risk of cardiovascular disease and how glycation might be targeted therapeutically. Glycation can affect the cardiomyocyte through extracellular mechanisms, including RAGE-based signaling, glycation of the extracellular matrix that modifies the mechanical environment, and signaling from the vasculature. Intracellular glycation of the cardiomyocyte can impact calcium handling, protein quality control and cell death pathways, as well as the cytoskeleton, resulting in a blunted contractility. While reducing protein glycation and its impact on the heart has been an active area of drug development, multiple clinical trials have had mixed results and these compounds have not been translated to the clinic-highlighting the challenges of modulating myocyte glycation. Here we will review protein glycation and its effects on the cardiomyocyte, therapeutic attempts to reverse these, and offer insight as to the future of glycation studies and patient treatment.
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Affiliation(s)
- Christine E Delligatti
- Department of Cell and Molecular Physiology, Loyola University Chicago Stritch School of Medicine, Maywood, IL, United States
| | - Jonathan A Kirk
- Department of Cell and Molecular Physiology, Loyola University Chicago Stritch School of Medicine, Maywood, IL, United States.
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6
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Dattani A, Singh A, McCann GP, Gulsin GS. Myocardial Calcium Handling in Type 2 Diabetes: A Novel Therapeutic Target. J Cardiovasc Dev Dis 2023; 11:12. [PMID: 38248882 PMCID: PMC10817027 DOI: 10.3390/jcdd11010012] [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: 11/06/2023] [Revised: 12/20/2023] [Accepted: 12/28/2023] [Indexed: 01/23/2024] Open
Abstract
Type 2 diabetes (T2D) is a multisystem disease with rapidly increasing global prevalence. Heart failure has emerged as a major complication of T2D. Dysregulated myocardial calcium handling is evident in the failing heart and this may be a key driver of cardiomyopathy in T2D, but until recently this has only been demonstrated in animal models. In this review, we describe the physiological concepts behind calcium handling within the cardiomyocyte and the application of novel imaging techniques for the quantification of myocardial calcium uptake. We take an in-depth look at the evidence for the impairment of calcium handling in T2D using pre-clinical models as well as in vivo studies, following which we discuss potential novel therapeutic approaches targeting dysregulated myocardial calcium handling in T2D.
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Affiliation(s)
- Abhishek Dattani
- Department of Cardiovascular Sciences, University of Leicester and NIHR Leicester Biomedical Research Centre, Leicester LE3 9QP, UK; (A.S.); (G.P.M.); (G.S.G.)
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7
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Xu N, Liu S, Zhang Y, Chen Y, Zuo Y, Tan X, Liao B, Li P, Feng J. Oxidative stress signaling in the pathogenesis of diabetic cardiomyopathy and the potential therapeutic role of antioxidant naringenin. Redox Rep 2023; 28:2246720. [PMID: 37747066 PMCID: PMC10538464 DOI: 10.1080/13510002.2023.2246720] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/26/2023] Open
Abstract
Diabetes mellitus (DM) is one of the most prevalent metabolic disorders that poses a global threat to human health. It can lead to complications in multiple organs and tissues, owing to its wide-ranging impact on the human body. Diabetic cardiomyopathy (DCM) is a specific cardiac manifestation of DM, which is characterized by heart failure in the absence of coronary heart disease, hypertension and valvular heart disease. Given that oxidative stress is a key factor in the pathogenesis of DCM, intervening to mitigate oxidative stress may serve as a therapeutic strategy for managing DCM. Naringenin is a natural product with anti-oxidative stress properties that can suppress oxidative damage by regulating various oxidative stress signaling pathways. In this review, we address the relationship between oxidative stress and its primary signaling pathways implicated in DCM, and explores the therapeutic potential of naringenin in DCM.
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Affiliation(s)
- Nan Xu
- Department of Cardiology, The First People's Hospital of Neijiang, Neijiang, People’s Republic of China
| | - Siqi Liu
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, People’s Republic of China
| | - Yongqiang Zhang
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, People’s Republic of China
| | - Yujing Chen
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, People’s Republic of China
| | - Yumei Zuo
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, People’s Republic of China
| | - Xiaoqiu Tan
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, People’s Republic of China
| | - Bin Liao
- Department of Cardiovascular Surgery, The Affiliated Hospital of Southwest Medical University, Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Luzhou, People’s Republic of China
| | - Pengyun Li
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, People’s Republic of China
| | - Jian Feng
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, People’s Republic of China
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8
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Zhi F, Zhang Q, Liu L, Chang X, Xu H. Novel insights into the role of mitochondria in diabetic cardiomyopathy: molecular mechanisms and potential treatments. Cell Stress Chaperones 2023; 28:641-655. [PMID: 37405612 PMCID: PMC10746653 DOI: 10.1007/s12192-023-01361-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 06/03/2023] [Accepted: 06/07/2023] [Indexed: 07/06/2023] Open
Abstract
Diabetic cardiomyopathy describes decreased myocardial function in diabetic patients in the absence of other heart diseases such as myocardial ischemia and hypertension. Recent studies have defined numerous molecular interactions and signaling events that may account for deleterious changes in mitochondrial dynamics and functions influenced by hyperglycemic stress. A metabolic switch from glucose to fatty acid oxidation to fuel ATP synthesis, mitochondrial oxidative injury resulting from increased mitochondrial ROS production and decreased antioxidant capacity, enhanced mitochondrial fission and defective mitochondrial fusion, impaired mitophagy, and blunted mitochondrial biogenesis are major signatures of mitochondrial pathologies during diabetic cardiomyopathy. This review describes the molecular alterations underlying mitochondrial abnormalities associated with hyperglycemia and discusses their influence on cardiomyocyte viability and function. Based on basic research findings and clinical evidence, diabetic treatment standards and their impact on mitochondrial function, as well as mitochondria-targeted therapies of potential benefit for diabetic cardiomyopathy patients, are also summarized.
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Affiliation(s)
- Fumin Zhi
- The First Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin, 150040, China
| | - Qian Zhang
- Heilongjiang University of Traditional Chinese Medicine, Harbin, 150040, China
| | - Li Liu
- The First Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin, 150040, China
| | - Xing Chang
- Guang'anmen Hospital of Chinese Academy of Traditional Chinese Medicine, Beijing, 100053, China.
| | - Hongtao Xu
- The First Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin, 150040, China.
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9
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Bansal S, Burman A, Tripathi AK. Advanced glycation end products: Key mediator and therapeutic target of cardiovascular complications in diabetes. World J Diabetes 2023; 14:1146-1162. [PMID: 37664478 PMCID: PMC10473940 DOI: 10.4239/wjd.v14.i8.1146] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 03/21/2023] [Accepted: 05/22/2023] [Indexed: 08/11/2023] Open
Abstract
The incidence of type 2 diabetes mellitus is growing in epidemic proportions and has become one of the most critical public health concerns. Cardiovascular complications associated with diabetes are the leading cause of morbidity and mortality. The cardiovascular diseases that accompany diabetes include angina, myocardial infarction, stroke, peripheral artery disease, and congestive heart failure. Among the various risk factors generated secondary to hyperglycemic situations, advanced glycation end products (AGEs) are one of the important targets for future diagnosis and prevention of diabetes. In the last decade, AGEs have drawn a lot of attention due to their involvement in diabetic patho-physiology. AGEs can be derived exogenously and endogenously through various pathways. These are a non-homogeneous, chemically diverse group of compounds formed non-enzymatically by condensation between carbonyl groups of reducing sugars and free amino groups of protein, lipids, and nucleic acid. AGEs mediate their pathological effects at the cellular and extracellular levels by multiple pathways. At the cellular level, they activate signaling cascades via the receptor for AGEs and initiate a complex series of intracellular signaling resulting in reactive oxygen species generation, inflammation, cellular proliferation, and fibrosis that may possibly exacerbate the damaging effects on cardiac functions in diabetics. AGEs also cause covalent modifications and cross-linking of serum and extracellular matrix proteins; altering their structure, stability, and functions. Early diagnosis of diabetes may prevent its progression to complications and decrease its associated comorbidities. In the present review, we recapitulate the role of AGEs as a crucial mediator of hyperglycemia-mediated detrimental effects in diabetes-associated complications. Furthermore, this review presents an overview of future perspectives for new therapeutic interventions to ameliorate cardiovascular complications in diabetes.
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Affiliation(s)
- Savita Bansal
- Department of Biochemistry, Institute of Home Sciences, University of Delhi, New Delhi 110016, India
| | - Archana Burman
- Department of Biochemistry, Institute of Home Economics, University of Delhi, New Delhi 110016, India
| | - Asok Kumar Tripathi
- Department of Biochemistry, University College of Medical Sciences, University of Delhi, New Delhi 110095, India
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10
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Maity J, Dey T, Banerjee A, Chattopadhyay A, Das AR, Bandyopadhyay D. Melatonin ameliorates myocardial infarction in obese diabetic individuals: The possible involvement of macrophage apoptotic factors. J Pineal Res 2023; 74:e12847. [PMID: 36456538 DOI: 10.1111/jpi.12847] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 10/14/2022] [Accepted: 11/28/2022] [Indexed: 12/05/2022]
Abstract
In recent days, the hike in obesity-mediated epidemics across the globe and the prevalence of obesity-induced cardiovascular disease has become one of the chief grounds for morbidity and mortality. This epidemic-driven detrimental events in the cardiac tissues start with the altered distribution and metabolism pattern of high-density lipoprotein and low-density lipoprotein (LDL) leading to cholesterol (oxidized LDL) deposition on the arterial wall and atherosclerotic plaque generation, followed by vascular spasms and infarction. Subsequently, obesity-triggered metabolic malfunctions induce free radical generation which may further trigger pro-inflammatory signaling and nuclear factor kappa-light-chain-enhancer of activated B cells transcriptional factor, thus inducing interferon-gamma, tumor necrosis factor-alpha, and inducible nitric oxide synthase. This terrifying cardiomyopathy can be further aggravated in type 2 diabetes mellitus, thereby making obese diabetic patients prone toward the development of myocardial infarction (MI) or stroke in comparison to their nondiabetic counterparts. The accelerated oxidative stress and pro-inflammatory response induced cardiomyocyte hypertrophy, followed by apoptosis in obese diabetic individuals, causing progression of athero-thrombotic vascular disease. Being an efficient antioxidative and anti-inflammatory indolamine, melatonin effectively inhibits lipid peroxidation, pro-inflammatory reactions, thereby resolving free radical-induced myocardial damages along with maintaining antioxidant reservoir to preserve cardiovascular integrity. Prolonged melatonin treatment maintains balanced body weight and serum total cholesterol concentration by inhibiting cholesterol synthesis and promoting cholesterol catabolism. Additionally, melatonin promotes macrophage polarization toward the anti-inflammatory state, providing a proper shield during the recovery period. Therefore, the protective role of melatonin in maintaining the lipid metabolism homeostasis and blocking the atherosclerotic plaque rupture could be targeted as the possible therapeutic strategy for the management of obesity-induced acute MI. This review aimed at orchestrating the efficacy of melatonin in ameliorating irrevocable oxidative cardiovascular damage induced by the obesity-diabetes correlation.
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Affiliation(s)
- Juin Maity
- Oxidative Stress and Free Radical Biology Laboratory, Department of Physiology, University of Calcutta, Kolkata, India
| | - Tiyasa Dey
- Oxidative Stress and Free Radical Biology Laboratory, Department of Physiology, University of Calcutta, Kolkata, India
| | - Adrita Banerjee
- Oxidative Stress and Free Radical Biology Laboratory, Department of Physiology, University of Calcutta, Kolkata, India
| | | | - Asish R Das
- Department of Chemistry, University of Calcutta, Kolkata, India
| | - Debasish Bandyopadhyay
- Oxidative Stress and Free Radical Biology Laboratory, Department of Physiology, University of Calcutta, Kolkata, India
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11
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D’Haese S, Deluyker D, Bito V. Acute Exposure to Glycated Proteins Impaired in the Endothelium-Dependent Aortic Relaxation: A Matter of Oxidative Stress. Int J Mol Sci 2022; 23:ijms232314916. [PMID: 36499244 PMCID: PMC9740119 DOI: 10.3390/ijms232314916] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 11/03/2022] [Accepted: 11/23/2022] [Indexed: 11/30/2022] Open
Abstract
Chronically increased levels of high molecular weight advanced glycation end products (HMW-AGEs) are known to induce cardiovascular dysfunction. Whether an acute increase in HMW-AGE levels affects vascular function remains unknown. In this study, we examined whether acute exposure to HMW-AGEs disturbs aortic vasomotor function. Aortae were obtained from healthy male rats and were acutely pre-treated with HMW-AGEs in organ baths. Aortic relaxation responses to cumulative doses of acetylcholine (ACh), in the presence or absence of superoxide dismutase (SOD), were measured after precontraction with phenylephrine (PE). Furthermore, levels of 3-nitrotyrosine were evaluated on aortic paraffine sections. In our study, we show that acute exposure to HMW-AGEs significantly decreases the aortic relaxation response to ACh. SOD pre-treatment prevents acute HMW-AGEs-induced impairment by limiting superoxide formation. In conclusion, our data demonstrate that acute exposure to HMW-AGEs causes adverse vascular remodelling, characterised by disturbed vasomotor function due to increased oxidative stress. These results create opportunities for future research regarding the acute role of HMW-AGEs in cardiovascular dysfunction.
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12
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Aftermath of AGE-RAGE Cascade in the pathophysiology of cardiovascular ailments. Life Sci 2022; 307:120860. [PMID: 35940220 DOI: 10.1016/j.lfs.2022.120860] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Revised: 07/20/2022] [Accepted: 08/01/2022] [Indexed: 11/21/2022]
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13
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Singh S, Siva BV, Ravichandiran V. Advanced Glycation End Products: key player of the pathogenesis of atherosclerosis. Glycoconj J 2022; 39:547-563. [PMID: 35579827 DOI: 10.1007/s10719-022-10063-x] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 04/07/2022] [Accepted: 05/02/2022] [Indexed: 01/08/2023]
Abstract
Atherosclerosis is the most common type of cardiovascular disease, and it causes intima thickening, plaque development, and ultimate blockage of the artery lumen. Advanced glycation end products (AGEs) are thought to have a role in the development and progression of atherosclerosis. there is developing an enthusiasm for AGEs as a potential remedial target. AGES mainly induce arterial damage and exacerbate the development of atherosclerotic plaques by triggering cell receptor-dependent signalling. The interplay of AGEs with RAGE, a transmembrane signalling receptor present across all cells important to atherosclerosis, changes cell activity, boosts expression of genes, and increases the outflow of inflammatory compounds, resulting in arterial wall injury and plaque formation. Here in this review, function of AGEs in the genesis, progression, and instability of atherosclerosis is discussed. In endothelial and smooth muscle cells, as well as platelets, the interaction of AGEs with their transmembrane cell receptor, RAGE, triggers intracellular signalling, resulting in endothelial damage, vascular smooth muscle cell function modification, and changed platelet activity.
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Affiliation(s)
- Sanjiv Singh
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Export Promotion Industrial Park (EPIP) Zandaha Road, 844102, Dist:Vaishali, Hajipur, Bihar, India.
| | - Boddu Veerabadra Siva
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Export Promotion Industrial Park (EPIP) Zandaha Road, 844102, Dist:Vaishali, Hajipur, Bihar, India
| | - V Ravichandiran
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Export Promotion Industrial Park (EPIP) Zandaha Road, 844102, Dist:Vaishali, Hajipur, Bihar, India
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14
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Costa GC, Montagnoli TL, Da Silva JS, de Alencar AKN, Reina Gamba LE, Alves BEO, da Silva MMC, Trachez MM, do Nascimento JHM, Pimentel-Coelho PM, Mendez-Otero R, Lima LM, Barreiro EJ, Sudo RT, Zapata-Sudo G. New Benzofuran N-Acylhydrazone Reduces Cardiovascular Dysfunction in Obese Rats by Blocking TNF-Alpha Synthesis. DRUG DESIGN DEVELOPMENT AND THERAPY 2020; 14:3337-3350. [PMID: 32884238 PMCID: PMC7443037 DOI: 10.2147/dddt.s258459] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 06/22/2020] [Indexed: 12/26/2022]
Abstract
Introduction Diabetic obese patients are susceptible to the development of cardiovascular disease, including hypertension and cardiac dysfunction culminating in diabetic cardiomyopathy (DC), which represents a life-threatening health problem with increased rates of morbidity and mortality. The aim of the study is to characterize the effects of a new benzofuran N-acylhydrazone compound, LASSBio-2090, on metabolic and cardiovascular alterations in Zucker diabetic fatty (ZDF) rats presenting DC. Methods Male non-diabetic lean Zucker rats (ZL) and ZDF rats treated with vehicle (dimethylsulfoxide) or LASSBio-2090 were used in this study. Metabolic parameters, cardiovascular function, left ventricle histology and inflammatory protein expression were analyzed in the experimental groups. Results LASSBio-2090 administration in ZDF rats reduced glucose levels to 85.0 ± 1.7 mg/dL (p < 0.05). LASSBio-2090 also lowered the cholesterol and triglyceride levels from 177.8 ± 31.2 to 104.8 ± 5.3 mg/dL and from 123.0 ± 11.4 to 90.9 ± 4.8 mg/dL, respectively, in obese diabetic rats (p < 0.05). LASSBio-2090 normalized plasma insulin, insulin sensitivity and endothelial function in aortas from diabetic animals (p < 0.05). It also enhanced systolic and diastolic left-ventricular function and reverted myocardial remodeling by blocking the threefold elevation of TNF-α levels in hearts from ZDF rats. Conclusion LASSBio-2090 alleviates metabolic disturbance and cardiomyopathy in an obese and diabetic rat model, thus representing a novel strategy for the treatment of cardiovascular complications in obesity-associated type 2 diabetes mellitus.
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Affiliation(s)
- Gizele Cabral Costa
- Programa de Pós-Graduação em Medicina (Cardiologia), Instituto do Coração Edson Saad, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Tadeu Lima Montagnoli
- Programa de Pesquisa em Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Jaqueline Soares Da Silva
- Programa de Pesquisa em Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Allan Kardec Nogueira de Alencar
- Programa de Pesquisa em Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Luis Eduardo Reina Gamba
- Programa de Pesquisa em Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Bryelle Eccard Oliveira Alves
- Programa de Pós-Graduação em Medicina (Cardiologia), Instituto do Coração Edson Saad, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil.,Programa de Pesquisa em Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Marina Moraes Carvalho da Silva
- Programa de Pesquisa em Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Margarete Manhães Trachez
- Programa de Pesquisa em Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - José Hamilton M do Nascimento
- Programa de Pesquisa em Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil.,Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Pedro Moreno Pimentel-Coelho
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Rosália Mendez-Otero
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Lidia Moreira Lima
- Programa de Pesquisa em Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Eliezer J Barreiro
- Programa de Pesquisa em Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Roberto Takashi Sudo
- Programa de Pesquisa em Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Gisele Zapata-Sudo
- Programa de Pós-Graduação em Medicina (Cardiologia), Instituto do Coração Edson Saad, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil.,Programa de Pesquisa em Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
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15
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Role of Non-coding RNA in Diabetic Cardiomyopathy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1229:181-195. [PMID: 32285412 DOI: 10.1007/978-981-15-1671-9_10] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Diabetic cardiomyopathy (DCM) is the leading cause of morbidity and mortality in diabetic population worldwide, characteristic by cardiomyocyte hypertrophy, apoptosis and myocardial interstitial fibrosis and eventually developing into heart failure. Non-coding RNAs, such as microRNAs (miRNAs), circular RNAs (circRNAs), long non-coding RNAs (lncRNAs) and other RNAs without the protein encoding function were emerging as a popular regulator in various types of processes during human diseases. The evidences have shown that miRNAs are regulators in diabetic cardiomyopathy, such as insulin resistance, cardiomyocytes apoptosis, and inflammatory, especially their protective effect on heart function. Besides that, the functions of lncRNAs and circRNAs have been gradually confirmed in recent years, and their functions in DCM have become increasingly prominent. We highlighted the nonnegligible roles of non-coding RNAs in the pathological process of DCM and showed the future possibilities of these non-coding RNAs in DCM treatment. In this chapter, we summarized the present advance of the researches in this filed and raised the concern and the prospect in the future.
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Diabetic Cardiomyopathy and Ischemic Heart Disease: Prevention and Therapy by Exercise and Conditioning. Int J Mol Sci 2020; 21:ijms21082896. [PMID: 32326182 PMCID: PMC7215312 DOI: 10.3390/ijms21082896] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Revised: 04/14/2020] [Accepted: 04/18/2020] [Indexed: 02/06/2023] Open
Abstract
Metabolic syndrome, diabetes, and ischemic heart disease are among the leading causes of death and disability in Western countries. Diabetic cardiomyopathy is responsible for the most severe signs and symptoms. An important strategy for reducing the incidence of cardiovascular disease is regular exercise. Remote ischemic conditioning has some similarity with exercise and can be induced by short periods of ischemia and reperfusion of a limb, and it can be performed in people who cannot exercise. There is abundant evidence that exercise is beneficial in diabetes and ischemic heart disease, but there is a need to elucidate the specific cardiovascular effects of emerging and unconventional forms of exercise in people with diabetes. In addition, remote ischemic conditioning may be considered among the options to induce beneficial effects in these patients. The characteristics and interactions of diabetes and ischemic heart disease, and the known effects of exercise and remote ischemic conditioning in the presence of metabolic syndrome and diabetes, are analyzed in this brief review.
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Al Kury LT. Calcium Homeostasis in Ventricular Myocytes of Diabetic Cardiomyopathy. J Diabetes Res 2020; 2020:1942086. [PMID: 33274235 PMCID: PMC7683117 DOI: 10.1155/2020/1942086] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 10/24/2020] [Accepted: 10/29/2020] [Indexed: 12/12/2022] Open
Abstract
Diabetes mellitus (DM) is a chronic metabolic disorder commonly characterized by high blood glucose levels, resulting from defects in insulin production or insulin resistance, or both. DM is a leading cause of mortality and morbidity worldwide, with diabetic cardiomyopathy as one of its main complications. It is well established that cardiovascular complications are common in both types of diabetes. Electrical and mechanical problems, resulting in cardiac contractile dysfunction, are considered as the major complications present in diabetic hearts. Inevitably, disturbances in the mechanism(s) of Ca2+ signaling in diabetes have implications for cardiac myocyte contraction. Over the last decade, significant progress has been made in outlining the mechanisms responsible for the diminished cardiac contractile function in diabetes using different animal models of type I diabetes mellitus (TIDM) and type II diabetes mellitus (TIIDM). The aim of this review is to evaluate our current understanding of the disturbances of Ca2+ transport and the role of main cardiac proteins involved in Ca2+ homeostasis in the diabetic rat ventricular cardiomyocytes. Exploring the molecular mechanism(s) of altered Ca2+ signaling in diabetes will provide an insight for the identification of novel therapeutic approaches to improve the heart function in diabetic patients.
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Affiliation(s)
- Lina T. Al Kury
- Department of Health Sciences, College of Natural and Health Sciences, Zayed University, Abu Dhabi 144534, UAE
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18
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Mechanical strength determines Ca 2+ transients triggered by the engagement of β 2 integrins to their ligands. Exp Cell Res 2019; 387:111807. [PMID: 31891683 DOI: 10.1016/j.yexcr.2019.111807] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 12/26/2019] [Accepted: 12/27/2019] [Indexed: 01/13/2023]
Abstract
Lymphocyte function-associated antigen-1 (LFA-1) and macrophage-1 antigen (Mac-1) are key adhesion receptors to mediate neutrophil (PMN) recruitment and intracellular calcium (Ca2+) signaling. Binding of LFA-1 and Mac-1 to their ligands is essential in triggering Ca2+ transients and activating Ca2+-dependent kinases involved in cytoskeletal remodeling and migratory function. While mechanical forces are critical in regulating integrin-mediated Ca2+ transients, it is still unclear how the bond strength of β2-integrin-ligand pair affects Ca2+ responses. Here three typical ligands with known mechanical features with LFA-1 and Mac-1 in our previous work were adopted to quantify their capabilities in inducing Ca2+ transients in adherent PMNs under shear flow. Data indicated that LFA-1 dominates Ca2+ transients in PMNs on intercellular adhesive molecule 1 (ICAM-1) and junctional adhesion molecule-A (JAM-A), while Mac-1 mediates Ca2+ transients induced by receptor for advanced glycation end products (RAGE), consistent with their corresponding bond strengths. These results link β2 integrin-ligand bond strength with Ca2+ transients in PMNs, suggesting high bond strength gives rise to strong Ca2+ response especially under physiological-like shear flow. The outcomes provide a new insight in understanding the mechanical regulatory mechanisms of PMN recruitment.
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19
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Advanced Glycation End Products: Potential Mechanism and Therapeutic Target in Cardiovascular Complications under Diabetes. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:9570616. [PMID: 31885827 PMCID: PMC6925928 DOI: 10.1155/2019/9570616] [Citation(s) in RCA: 81] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Accepted: 11/25/2019] [Indexed: 01/08/2023]
Abstract
The occurrence and development of cardiovascular complications are predominantly responsible for the increased morbidity and mortality observed in patients with diabetes. Oxidative stress under hyperglycemia is currently considered the initial link to diabetic cardiovascular complications and a key node for the prevention and treatment of diabetes-related fatal cardiovascular events. Numerous studies have indicated that the common upstream pathway in the context of oxidative stress in the cardiovascular system under diabetic conditions is the interaction of advanced glycation end products (AGEs) with their receptors (RAGEs). Therefore, a further understanding of the relationship between oxidative stress and AGEs is of great significance for the prevention and treatment of cardiovascular complications in patients with diabetes. In this review, we will briefly summarize the recent research advances in diabetes with an emphasis on oxidative stress and its association with AGEs in diabetic cardiovascular complications.
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20
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Lee TW, Kao YH, Chen YJ, Chao TF, Lee TI. Therapeutic potential of vitamin D in AGE/RAGE-related cardiovascular diseases. Cell Mol Life Sci 2019; 76:4103-4115. [PMID: 31250032 PMCID: PMC11105755 DOI: 10.1007/s00018-019-03204-3] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Revised: 06/15/2019] [Accepted: 06/19/2019] [Indexed: 12/18/2022]
Abstract
Cardiovascular diseases (CVDs) are among the leading threats to human health. The advanced glycation end product (AGE) and receptor for AGE (RAGE) signaling pathway regulates the pathogenesis of CVDs, through its effects on arterial stiffness, atherosclerosis, mitochondrial dysfunction, oxidative stress, calcium homeostasis, and cytoskeletal function. Targeting the AGE/RAGE pathway is a potential therapeutic strategy for ameliorating CVDs. Vitamin D has several beneficial effects on the cardiovascular system. Experimental findings have shown that vitamin D regulates AGE/RAGE signaling and its downstream effects. This article provides a comprehensive review of the mechanistic insights into AGE/RAGE involvement in CVDs and the modulation of the AGE/RAGE signaling pathways by vitamin D.
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Affiliation(s)
- Ting-Wei Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, 111 Xinglong Road, Section 3 Wenshan District, Taipei, 11696, Taiwan
| | - Yu-Hsun Kao
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
| | - Yi-Jen Chen
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Cardiovascular Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
- Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Tze-Fan Chao
- Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- Institute of Clinical Medicine and Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan
| | - Ting-I Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, 111 Xinglong Road, Section 3 Wenshan District, Taipei, 11696, Taiwan.
- Department of General Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
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21
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Braidy N, Berg J, Clement J, Khorshidi F, Poljak A, Jayasena T, Grant R, Sachdev P. Role of Nicotinamide Adenine Dinucleotide and Related Precursors as Therapeutic Targets for Age-Related Degenerative Diseases: Rationale, Biochemistry, Pharmacokinetics, and Outcomes. Antioxid Redox Signal 2019; 30:251-294. [PMID: 29634344 PMCID: PMC6277084 DOI: 10.1089/ars.2017.7269] [Citation(s) in RCA: 153] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Revised: 02/22/2018] [Accepted: 02/22/2018] [Indexed: 12/20/2022]
Abstract
Significance: Nicotinamide adenine dinucleotide (NAD+) is an essential pyridine nucleotide that serves as an essential cofactor and substrate for a number of critical cellular processes involved in oxidative phosphorylation and ATP production, DNA repair, epigenetically modulated gene expression, intracellular calcium signaling, and immunological functions. NAD+ depletion may occur in response to either excessive DNA damage due to free radical or ultraviolet attack, resulting in significant poly(ADP-ribose) polymerase (PARP) activation and a high turnover and subsequent depletion of NAD+, and/or chronic immune activation and inflammatory cytokine production resulting in accelerated CD38 activity and decline in NAD+ levels. Recent studies have shown that enhancing NAD+ levels can profoundly reduce oxidative cell damage in catabolic tissue, including the brain. Therefore, promotion of intracellular NAD+ anabolism represents a promising therapeutic strategy for age-associated degenerative diseases in general, and is essential to the effective realization of multiple benefits of healthy sirtuin activity. The kynurenine pathway represents the de novo NAD+ synthesis pathway in mammalian cells. NAD+ can also be produced by the NAD+ salvage pathway. Recent Advances: In this review, we describe and discuss recent insights regarding the efficacy and benefits of the NAD+ precursors, nicotinamide (NAM), nicotinic acid (NA), nicotinamide riboside (NR), and nicotinamide mononucleotide (NMN), in attenuating NAD+ decline in degenerative disease states and physiological aging. Critical Issues: Results obtained in recent years have shown that NAD+ precursors can play important protective roles in several diseases. However, in some cases, these precursors may vary in their ability to enhance NAD+ synthesis via their location in the NAD+ anabolic pathway. Increased synthesis of NAD+ promotes protective cell responses, further demonstrating that NAD+ is a regulatory molecule associated with several biochemical pathways. Future Directions: In the next few years, the refinement of personalized therapy for the use of NAD+ precursors and improved detection methodologies allowing the administration of specific NAD+ precursors in the context of patients' NAD+ levels will lead to a better understanding of the therapeutic role of NAD+ precursors in human diseases.
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Affiliation(s)
- Nady Braidy
- Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia
| | - Jade Berg
- Australasian Research Institute, Sydney Adventist Hospital, Sydney, Australia
| | | | - Fatemeh Khorshidi
- Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia
| | - Anne Poljak
- Mark Wainwright Analytical Centre, University of New South Wales, Sydney, Australia
- School of Medical Sciences, University of New South Wales, Sydney, Australia
| | - Tharusha Jayasena
- Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia
| | - Ross Grant
- Australasian Research Institute, Sydney Adventist Hospital, Sydney, Australia
- School of Medical Sciences, University of New South Wales, Sydney, Australia
- Sydney Medical School, University of Sydney, Sydney, Australia
| | - Perminder Sachdev
- Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia
- Neuropsychiatric Institute, Euroa Centre, Prince of Wales Hospital, Sydney, Australia
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Chang GJ, Yeh YH, Chen WJ, Ko YS, Pang JHS, Lee HY. Inhibition of Advanced Glycation End Products Formation Attenuates Cardiac Electrical and Mechanical Remodeling and Vulnerability to Tachyarrhythmias in Diabetic Rats. J Pharmacol Exp Ther 2019; 368:66-78. [PMID: 30381326 DOI: 10.1124/jpet.118.252080] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Accepted: 10/23/2018] [Indexed: 03/08/2025] Open
Abstract
Diabetic patients with cardiomyopathy show a higher incidence of arrhythmias and sudden death. Chronic hyperglycemia induces the formation of advanced glycation end products (AGEs), which contribute to the pathogenesis of diabetic cardiomyopathy. This study investigated whether inhibition of AGEs formation by aminoguanidine (AG) could prevent cardiac electromechanical and arrhythmogenic remodeling in diabetes mellitus. Streptozotocin-induced diabetic rats received AG (100 mg/kg daily, i.p.) or vehicle (normal saline, i.p.) for 5 weeks. The rats underwent hemodynamic recording to evaluate cardiac function, and heart preparations were used to determine the electrical, mechanical, and biochemical functions. In vitro high glucose-induced AGEs formation, reactive oxygen species (ROS) generation, and action potential changes were examined in HL-1 atrial cells. AG treatment improved the diabetes-induced depression in left ventricular pressure and the relaxation rate, and normalized the prolongation of QTc intervals in anesthetized rats. AG reduced the vulnerabilities to atrial and ventricular tachyarrhythmias in perfused diabetic hearts. AG normalized the prolonged action potential duration in diabetic atrial and ventricular muscles, which was correlated with the restoration of both transient outward (I to) and steady-state outward (I SS) K+ current densities in cardiomyocytes. The abnormal kinetics of Ca2+ transients and contraction were reversed in cardiomyocytes from AG-treated diabetic rats, along with parallel preservation of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2a) expression. Furthermore, ex vivo and in vitro studies showed AG attenuated AGEs and ROS formation. Thus, long-term administration of AG ameliorated cardiac electromechanical remodeling and arrhythmogenicity in diabetic rats and may present an effective strategy for the prevention of diabetes-associated arrhythmias.
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Affiliation(s)
- Gwo-Jyh Chang
- Graduate Institute of Clinical Medicinal Sciences, College of Medicine, Chang Gung University (G.-J.C., J.-H.S.P., H.-Y.L.), and Cardiovascular Medicine, Chang Gung Memorial Hospital (G.-J.C., Y.-H.Y., W.-J.C., Y.-S.K.), Tao-Yuan, Taiwan
| | - Yung-Hsin Yeh
- Graduate Institute of Clinical Medicinal Sciences, College of Medicine, Chang Gung University (G.-J.C., J.-H.S.P., H.-Y.L.), and Cardiovascular Medicine, Chang Gung Memorial Hospital (G.-J.C., Y.-H.Y., W.-J.C., Y.-S.K.), Tao-Yuan, Taiwan
| | - Wei-Jan Chen
- Graduate Institute of Clinical Medicinal Sciences, College of Medicine, Chang Gung University (G.-J.C., J.-H.S.P., H.-Y.L.), and Cardiovascular Medicine, Chang Gung Memorial Hospital (G.-J.C., Y.-H.Y., W.-J.C., Y.-S.K.), Tao-Yuan, Taiwan
| | - Yu-Shien Ko
- Graduate Institute of Clinical Medicinal Sciences, College of Medicine, Chang Gung University (G.-J.C., J.-H.S.P., H.-Y.L.), and Cardiovascular Medicine, Chang Gung Memorial Hospital (G.-J.C., Y.-H.Y., W.-J.C., Y.-S.K.), Tao-Yuan, Taiwan
| | - Jong-Hwei S Pang
- Graduate Institute of Clinical Medicinal Sciences, College of Medicine, Chang Gung University (G.-J.C., J.-H.S.P., H.-Y.L.), and Cardiovascular Medicine, Chang Gung Memorial Hospital (G.-J.C., Y.-H.Y., W.-J.C., Y.-S.K.), Tao-Yuan, Taiwan
| | - Hsiao-Yu Lee
- Graduate Institute of Clinical Medicinal Sciences, College of Medicine, Chang Gung University (G.-J.C., J.-H.S.P., H.-Y.L.), and Cardiovascular Medicine, Chang Gung Memorial Hospital (G.-J.C., Y.-H.Y., W.-J.C., Y.-S.K.), Tao-Yuan, Taiwan
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Reduced Susceptibility to Sugar-Induced Metabolic Derangements and Impairments of Myocardial Redox Signaling in Mice Chronically Fed with D-Tagatose when Compared to Fructose. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:5042428. [PMID: 30327714 PMCID: PMC6169220 DOI: 10.1155/2018/5042428] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Accepted: 08/12/2018] [Indexed: 01/03/2023]
Abstract
Background D-tagatose is an isomer of fructose and is ~90% as sweet as sucrose with less caloric value. Nowadays, D-tagatose is used as a nutritive or low-calorie sweetener. Despite clinical findings suggesting that D-tagatose could be beneficial in subjects with type 2 diabetes, there are no experimental data comparing D-tagatose with fructose, in terms of metabolic derangements and related molecular mechanisms evoked by chronic exposure to these two monosaccharides. Materials and methods C57Bl/6j mice were fed with a control diet plus water (CD), a control diet plus 30% fructose syrup (L-Fr), a 30% fructose solid diet plus water (S-Fr), a control diet plus 30% D-tagatose syrup (L-Tg), or a 30% D-tagatose solid diet plus water (S-Tg), during 24 weeks. Results Both solid and liquid fructose feeding led to increased body weight, abnormal systemic glucose homeostasis, and an altered lipid profile. These effects were associated with vigorous increase in oxidative markers. None of these metabolic abnormalities were detected when mice were fed with both the solid and liquid D-tagatose diets, either at the systemic or at the local level. Interestingly, both fructose formulations led to significant Advanced Glycation End Products (AGEs) accumulation in mouse hearts, as well as a robust increase in both myocardial AGE receptor (RAGE) expression and NF-κB activation. In contrast, no toxicological effects were shown in hearts of mice chronically exposed to liquid or solid D-tagatose. Conclusion Our results clearly suggest that chronic overconsumption of D-tagatose in both formulations, liquid or solid, does not exert the same deleterious metabolic derangements evoked by fructose administration, due to differences in carbohydrate interference with selective proinflammatory and oxidative stress cascades.
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