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Fang H, Rai A, Eslami SS, Huynh K, Liao HC, Salim A, Greening DW. Proteomics and Machine Learning-Based Approach to Decipher Subcellular Proteome of Mouse Heart. Mol Cell Proteomics 2025; 24:100952. [PMID: 40113211 PMCID: PMC12019842 DOI: 10.1016/j.mcpro.2025.100952] [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: 07/13/2024] [Revised: 02/19/2025] [Accepted: 03/16/2025] [Indexed: 03/22/2025] Open
Abstract
Protein compartmentalization to distinctive subcellular niches is critical for cardiac function and homeostasis. Here, we employed a rapid and robust workflow based on differential centrifugal-based fractionation with mass spectrometry-based proteomics and bioinformatic analyses for systemic mapping of the subcellular proteome of mouse heart. Using supervised machine learning of 450 hallmark protein markers from 16 subcellular niches, we further refined the subcellular information of 2083 proteins with high confidence. Our data validation focused on specific subcellular niches such as mitochondria, cell surface, cardiac dyad, myofibril, and nuclear, unfolding dominant subcellular localization of proteins in their native environment of mouse heart. We further provide targeted nuclear enrichment and co-immunoprecipitation-based proteomic validation from the heart of nuclear-localizing protein networks. This study provides novel insights into the molecular landscape of different subcellular niches of the heart and serves as a draft map for heart subcellular proteome.
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Affiliation(s)
- Haoyun Fang
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia; Baker Department of Cardiometabolic Health, University of Melbourne, Parkville, Victoria, Australia
| | - Alin Rai
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia; Baker Department of Cardiometabolic Health, University of Melbourne, Parkville, Victoria, Australia; Baker Department of Cardiovascular Research Translation and Implementation, La Trobe University, Bundoora, Victoria, Australia
| | - Seyed Sadegh Eslami
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia; Baker Department of Cardiovascular Research Translation and Implementation, La Trobe University, Bundoora, Victoria, Australia
| | - Kevin Huynh
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia; Baker Department of Cardiometabolic Health, University of Melbourne, Parkville, Victoria, Australia; Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Australia
| | - Hsiao-Chi Liao
- School of Mathematics and Statistics, The University of Melbourne, Parkville, Victoria, Australia
| | - Agus Salim
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia; Melbourne School of Population and Global Health, University of Melbourne, Parkville, Victoria, Australia; School of Mathematics and Statistics, The University of Melbourne, Parkville, Victoria, Australia
| | - David W Greening
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia; Baker Department of Cardiometabolic Health, University of Melbourne, Parkville, Victoria, Australia; Baker Department of Cardiovascular Research Translation and Implementation, La Trobe University, Bundoora, Victoria, Australia.
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Zhen WJ, Zhang Y, Fu WD, Fu XL, Yan X. Role of immune-related endoplasmic reticulum stress genes in sepsis-induced cardiomyopathy: Novel insights from bioinformatics analysis. PLoS One 2024; 19:e0315582. [PMID: 39671358 PMCID: PMC11642931 DOI: 10.1371/journal.pone.0315582] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Accepted: 11/27/2024] [Indexed: 12/15/2024] Open
Abstract
BACKGROUND The current study aims to elucidate the key molecular mechanisms linked to endoplasmic reticulum stress (ERS) in the pathogenesis of sepsis-induced cardiomyopathy (SIC) and offer innovative therapeutic targets for SIC. METHODS The study downloaded dataset GSE79962 from the Gene Expression Omnibus database and acquired the ERS-related gene set from GeneCards. It utilized weighted gene co-expression network analysis (WGCNA) and conducted differential expression analysis to identify key modules and genes associated with SIC. The SIC hub genes were determined by the intersection of WGCNA-based hubs, DEGs, and ERS-related genes, followed by protein-protein interaction (PPI) network construction. Enrichment analyses, encompassing GO, KEGG, GSEA, and GSVA, were performed to elucidate potential biological pathways. The CIBERSORT algorithm was employed to analyze immune infiltration patterns. Diagnostic and prognostic models were developed to assess the clinical significance of hub genes in SIC. Additionally, in vivo experiments were conducted to validate the expression of hub genes. RESULTS Differential analysis revealed 1031 differentially expressed genes (DEGs), while WGCNA identified a hub module with 1327 key genes. Subsequently, 13 hub genes were pinpointed by intersecting with ERS-related genes. NOX4, PDHB, SCP2, ACTC1, DLAT, EDN1, and NSDHL emerged as hub ERS-related genes through the protein-protein interaction network, with their diagnostic values confirmed via ROC curves. Diagnostic models incorporating five genes (NOX4, PDHB, ACTC1, DLAT, NSDHL) were validated using the LASSO algorithm, highlighting only the prognostic significance of serum PDHB levels in predicting the survival of septic patients. Additionally, decreased PDHB mRNA and protein expression levels were observed in the cardiac tissue of septic mice compared to control mice. CONCLUSIONS This study elucidated the interplay between metabolism and the immune microenvironment in SIC, providing fresh perspectives on the investigation of potential SIC pathogenesis. PDHB emerged as a significant biomarker of SIC, with implications on its progression through the regulation of ERS and metabolism.
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Affiliation(s)
- Wan-Jing Zhen
- Department of Anesthesiology, the Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, China
| | - Yan Zhang
- Department of Anesthesiology, Zhuzhou Central Hospital (Zhuzhou Hospital Affiliated to Xiangya School of Medicine), Zhuzhou, Hunan Province, China
| | - Wei-Dong Fu
- Department of Anesthesiology, Zhuzhou Central Hospital (Zhuzhou Hospital Affiliated to Xiangya School of Medicine), Zhuzhou, Hunan Province, China
| | - Xiao-Lei Fu
- Department of Cardiovascular Medicine, Zhuzhou Central Hospital (Zhuzhou Hospital Affiliated to Xiangya School of Medicine), Zhuzhou, Hunan Province, China
| | - Xin Yan
- Department of Cardiovascular Medicine, Zhuzhou Central Hospital (Zhuzhou Hospital Affiliated to Xiangya School of Medicine), Zhuzhou, Hunan Province, China
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Wang F, Wang J, Liang X, Wu Z, Xue J, Yin L, Wei L, Zhang X. Ghrelin inhibits myocardial pyroptosis in diabetic cardiomyopathy by regulating ERS and NLRP3 inflammasome crosstalk through the PI3K/AKT pathway. J Drug Target 2024; 32:148-158. [PMID: 38088811 DOI: 10.1080/1061186x.2023.2295268] [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: 09/08/2023] [Accepted: 12/10/2023] [Indexed: 12/20/2023]
Abstract
AIMS Endoplasmic reticulum stress(ERS) can induce inflammation mediated by NLRP3 inflammatory bodies and link inflammation with oxidative stress in myocardial tissue. Ghrelin is an endogenous growth hormone-releasing peptide that has been proven to have multiple effects, such as regulating energy metabolism and inhibiting inflammation. However, the role of ghrelin in myocardial injury in diabetic rats and the mechanism have not been reported. RESULTS We found that ghrelin could improve endoplasmic reticulum stress and inflammatory pyroptosis in the myocardial tissue of diabetic rats and reduce ERS and NLRP3 inflammasome crosstalk in H9C2 cardiomyocytes. Interestingly, ghrelin could activate the PI3K/AKT signalling pathway, playing a role in inhibiting endoplasmic reticulum stress and reducing the expression of pyroptosis-related proteins. However, these protective effects could be largely eliminated by LY294002. CONCLUSIONS In summary, we demonstrated that ghrelin inhibited myocardial pyroptosis in diabetic cardiomyopathy by regulating ERS and NLRP3 inflammasome crosstalk through the PI3K/AKT pathway. Our results provide new insights into the mechanism of diabetic myocardial injury induced by high glucose and high palmitic acid and ghrelin-mediated anti-inflammatory protection and provide potential therapeutic targets and strategies for diabetic cardiomyopathy.
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Affiliation(s)
- Fan Wang
- The Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Jingzhi Wang
- The Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xinfang Liang
- The Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Zixuan Wu
- The Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Jiaxin Xue
- The Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Lingyu Yin
- The Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Lai Wei
- The Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xiaohui Zhang
- The Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
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Safavi K, Hajibabaie F, Abedpoor N. Bioinformatics and Chemoinformatics Analysis Explored the Role of Linum usitatissimum in Diabetic Heart Conditions: Experimental Analysis in H9c2 Rat Embryonic Cardiomyocytes Cell Lines. JOURNAL OF MEDICAL SIGNALS & SENSORS 2024; 14:27. [PMID: 39380770 PMCID: PMC11460736 DOI: 10.4103/jmss.jmss_4_24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 03/18/2024] [Accepted: 05/27/2024] [Indexed: 10/10/2024]
Abstract
Background Cytokine storms and inflammation lead to heart failure (HF). Bioactive compounds, as complementary medicine, can be the primary source of compounds with anti-inflammatory properties. Linum usitatissimum (LiU) has antioxidant capacity and anti-inflammatory activity. Here, candidate hugeness was selected based on the in silico studies, bio-cheminformatics, and bioinformatic analysis for excremental validation. Methods We selected the vital genes with differential expression from the GSE26887 dataset. Based on the bioinformatics analysis, several parameters are determined to choose switchable genes involved in diabetic HF (DHF). We designed the protein-protein interactions network to consider the nodes' degree, modularity, and betweenness centrality. Hence, we selected the interleukin (IL)-6 protein as a target for drug design and discovery to reduce diabetes complications in the heart. Here, H9c2 cell lines of rat embryonic cardiomyocytes induce HF using hyperglycemic and hyperlipidemic conditions. Real-time polymerase chain reaction evaluated the relative expression of SMAD7/NRF-2/STAT3. Furthermore, we assessed the concentration of IL-6 using the enzyme-linked immunosorbent assay technique. Results Based on the bioinformatic analysis, we found that IL-6 with the highest network parameters score might be presented as a druggable protein in the DHF. Bioactive compounds and phytochemicals have potential strategies to manage DHF. LiUs decreased the expression level of the SMAD7 (P <0.0001) and STAT3 (P < 0.0001), and increased the expression level of the NRF2 (P < 0.0001). In addition, LiUs significantly reduced the concentration of IL-6 (P < 0.0001). Conclusion Our data proposed that LiUs regulated inflammation and triggered the antioxidant defense in HF. Moreover, LiUs could have potential approaches to managing and preventing DHF.
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Affiliation(s)
- Kamran Safavi
- Department of Plant Biotechnology, Medicinal Plants Research Centre, Isfahan (Khorasgan) Branch, Islamic Azad University, Isfahan, Iran
| | - Fatemeh Hajibabaie
- Department of Biology, Faculty of Basic Sciences, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
- Department of Physiology, Medicinal Plants Research Centre, Isfahan (Khorasgan) Branch, Islamic Azad University, Isfahan, Iran
| | - Navid Abedpoor
- Department of Physiology, Medicinal Plants Research Centre, Isfahan (Khorasgan) Branch, Islamic Azad University, Isfahan, Iran
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Liu Y, Xu C, Gu R, Han R, Li Z, Xu X. Endoplasmic reticulum stress in diseases. MedComm (Beijing) 2024; 5:e701. [PMID: 39188936 PMCID: PMC11345536 DOI: 10.1002/mco2.701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 07/30/2024] [Accepted: 07/31/2024] [Indexed: 08/28/2024] Open
Abstract
The endoplasmic reticulum (ER) is a key organelle in eukaryotic cells, responsible for a wide range of vital functions, including the modification, folding, and trafficking of proteins, as well as the biosynthesis of lipids and the maintenance of intracellular calcium homeostasis. A variety of factors can disrupt the function of the ER, leading to the aggregation of unfolded and misfolded proteins within its confines and the induction of ER stress. A conserved cascade of signaling events known as the unfolded protein response (UPR) has evolved to relieve the burden within the ER and restore ER homeostasis. However, these processes can culminate in cell death while ER stress is sustained over an extended period and at elevated levels. This review summarizes the potential role of ER stress and the UPR in determining cell fate and function in various diseases, including cardiovascular diseases, neurodegenerative diseases, metabolic diseases, autoimmune diseases, fibrotic diseases, viral infections, and cancer. It also puts forward that the manipulation of this intricate signaling pathway may represent a novel target for drug discovery and innovative therapeutic strategies in the context of human diseases.
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Affiliation(s)
- Yingying Liu
- Department of Aviation Clinical Medicine, Air Force Medical CenterPLABeijingChina
| | - Chunling Xu
- School of Pharmaceutical SciencesTsinghua UniversityBeijingChina
| | - Renjun Gu
- School of Chinese MedicineNanjing University of Chinese MedicineNanjingChina
- Department of Gastroenterology and HepatologyJinling HospitalMedical School of Nanjing UniversityNanjingChina
| | - Ruiqin Han
- State Key Laboratory of Medical Molecular BiologyDepartment of Biochemistry and Molecular BiologyInstitute of Basic Medical SciencesChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Ziyu Li
- School of Acupuncture and TuinaSchool of Regimen and RehabilitationNanjing University of Chinese MedicineNanjingChina
| | - Xianrong Xu
- Department of Aviation Clinical Medicine, Air Force Medical CenterPLABeijingChina
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Zheng J, Ma Y, Guo X, Wu J. Immunological characterization of stroke-heart syndrome and identification of inflammatory therapeutic targets. Front Immunol 2023; 14:1227104. [PMID: 37965346 PMCID: PMC10642553 DOI: 10.3389/fimmu.2023.1227104] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Accepted: 10/16/2023] [Indexed: 11/16/2023] Open
Abstract
Acute cardiac dysfunction caused by stroke-heart syndrome (SHS) is the second leading cause of stroke-related death. The inflammatory response plays a significant role in the pathophysiological process of cardiac damage. However, the mechanisms underlying the brain-heart interaction are poorly understood. Therefore, we aimed to analysis the immunological characterization and identify inflammation therapeutic targets of SHS. We analyzed gene expression data of heart tissue 24 hours after induction of ischemia stoke by MCAO or sham surgery in a publicly available dataset (GSE102558) from Gene Expression Omnibus (GEO). Bioinformatics analysis revealed 138 differentially expressed genes (DEGs) in myocardium of MCAO-treated compared with sham-treated mice, among which, immune and inflammatory pathways were enriched. Analysis of the immune cells infiltration showed that the natural killer cell populations were significantly different between the two groups. We identified five DIREGs, Aplnr, Ccrl2, Cdkn1a, Irak2, and Serpine1 and found that their expression correlated with specific populations of infiltrating immune cells in the cardiac tissue. RT-qPCR and Western blot methods confirmed significant changes in the expression levels of Aplnr, Cdkn1a, Irak2, and Serpine1 after MCAO, which may serve as therapeutic targets to prevent cardiovascular complications after stroke.
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Affiliation(s)
- Junyi Zheng
- Department of Cardiology, Tianjin Chest Hospital, Tianjin Institute of Cardiovascular Disease, Tianjin, China
- Chest Hospital, Tianjin University, Tianjin, China
| | - Yilin Ma
- Clinical College of Neurology, Neurosurgery and Neurorehabilitation, Tianjin Medical University, Tianjin, China
| | - Xukun Guo
- Department of Cardiology, Tianjin Chest Hospital, Tianjin Institute of Cardiovascular Disease, Tianjin, China
- Chest Hospital, Tianjin University, Tianjin, China
| | - Jialing Wu
- Department of Neurology, Department of Rehabilitation Medicine, Tianjin Neurosurgical Institute, Tianjin Huanhu Hospital, Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases, Tianjin, China
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Jo SL, Yang H, Lee HW, Hong EJ. Curcumae radix Reduces Endoplasmic Reticulum Stress in Mice with Chronic Neuroinflammation. Biomedicines 2023; 11:2107. [PMID: 37626603 PMCID: PMC10452873 DOI: 10.3390/biomedicines11082107] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 06/16/2023] [Accepted: 06/26/2023] [Indexed: 08/27/2023] Open
Abstract
Endoplasmic reticulum (ER) stress is a condition in which the ER protein-folding machinery is impaired, leading to the accumulation of improperly folded proteins and triggering an unfolded-protein response. Excessive ER stress causes cell death and contributes to the development of chronic diseases. Interestingly, there is a bidirectional relationship between ER stress and the nuclear factor-kappa B (NF-κB) pathway. Curcumin, a natural polyphenolic compound found in Curcumae radix, exerts its neuroprotective effects by regulating ER stress and inflammation. Therefore, investigating the potential protective and regulatory effects of curcumin on ER stress, inflammation, and neurodegeneration under chronic neuroinflammatory conditions is of great interest. Mice were pretreated with Curcumae radix extract (CRE) for 19 days and then treated with CRE plus lipopolysaccharide for 1 week. We monitored pro-inflammatory cytokine levels in the serum and ER stress-, inflammation-, and neurodegeneration-related markers in the mouse cerebrum and hippocampus using Western blotting and qRT-PCR. CRE reduced Interleukin-1 beta levels in the blood and brain of mice with lipopolysaccharide-induced chronic inflammation. CRE also suppressed the expression of markers related to the ER stress and NF-κB signaling pathways. The expression of neurodegeneration-related markers was reduced in the mouse cerebrum and hippocampus. CRE exerts neuroprotective effects under chronic inflammatory conditions via multifaceted anti-inflammatory and ER stress-pathway regulatory mechanisms.
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Affiliation(s)
- Seong-Lae Jo
- College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Republic of Korea;
| | - Hyun Yang
- KM Convergence Research Division, Korea Institute of Oriental Medicine, Daejeon 34054, Republic of Korea;
| | - Hye Won Lee
- KM Convergence Research Division, Korea Institute of Oriental Medicine, Daejeon 34054, Republic of Korea;
| | - Eui-Ju Hong
- College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Republic of Korea;
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Srinivas BK, Bourdi A, O'Regan JD, Malavalli KD, Rhaleb N, Belmadani S, Matrougui K. Interleukin-1β Disruption Protects Male Mice From Heart Failure With Preserved Ejection Fraction Pathogenesis. J Am Heart Assoc 2023; 12:e029668. [PMID: 37345828 PMCID: PMC10382083 DOI: 10.1161/jaha.122.029668] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Accepted: 04/18/2023] [Indexed: 06/23/2023]
Abstract
Background Heart failure with preserved ejection fraction (HFpEF) is a significant unmet need in cardiovascular medicine and remains an untreatable cardiovascular disease. The role and mechanism of interleukin-1β in HFpEF pathogenesis are poorly understood. Methods and Results C57/Bl6J and interleukin-1β-/- male mice were randomly divided into 4 groups. Groups 1 and 2: C57/Bl6J and interleukin-1β-/- mice were fed a regular diet for 4 months and considered controls. Groups 3 and 4: C57/Bl6 and interleukin-1β-/- mice were fed a high-fat diet with N[w]-nitro-l-arginine methyl ester (endothelial nitric oxide synthase inhibitor, 0.5 g/L) in the drinking water for 4 months. We measured body weight, blood pressure, diabetes status, cardiac function/hypertrophy/inflammation, fibrosis, vascular endothelial function, and signaling. C57/Bl6 fed a high-fat diet and N[w]-nitro-l-arginine methyl ester in the drinking water for 4 months developed HFpEF pathogenesis characterized by obesity, diabetes, hypertension, cardiac hypertrophy, lung edema, low running performance, macrovascular and microvascular endothelial dysfunction, and diastolic cardiac dysfunction but no change in cardiac ejection fraction compared with control mice. Interestingly, the genetic disruption of interleukin-1β protected mice from HFpEF pathogenesis through the modulation of the inflammation and endoplasmic reticulum stress mechanisms. Conclusions Our data suggest that interleukin-1β is a critical driver in the development of HFpEF pathogenesis, likely through regulating inflammation and endoplasmic reticulum stress pathways. Our findings provide a potential therapeutic target for HFpEF treatment.
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Affiliation(s)
| | - Aya Bourdi
- Department of Physiological SciencesEVMSNorfolkVAUSA
| | | | | | - Nour‐Eddine Rhaleb
- Hypertension & Vascular Research DivisionDepartment of Internal MedicineHenry Ford HealthDetroitMIUSA
- Department of PhysiologySchool of MedicineWayne State UniversityDetroitMIUSA
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Lin Z. More than a key-the pathological roles of SARS-CoV-2 spike protein in COVID-19 related cardiac injury. SPORTS MEDICINE AND HEALTH SCIENCE 2023:S2666-3376(23)00024-0. [PMID: 37361919 PMCID: PMC10062797 DOI: 10.1016/j.smhs.2023.03.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 03/13/2023] [Accepted: 03/22/2023] [Indexed: 06/28/2023] Open
Abstract
Cardiac injury is common in hospitalized coronavirus disease 2019 (COVID-19) patients and cardiac abnormalities have been observed in a significant number of recovered COVID-19 patients, portending long-term health issues for millions of infected individuals. To better understand how Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2, CoV-2 for short) damages the heart, it is critical to fully comprehend the biology of CoV-2 encoded proteins, each of which may play multiple pathological roles. For example, CoV-2 spike glycoprotein (CoV-2-S) not only engages angiotensin converting enzyme II (ACE2) to mediate virus infection but also directly activates immune responses. In this work, the goal is to review the known pathological roles of CoV-2-S in the cardiovascular system, thereby shedding lights on the pathogenesis of COVID-19 related cardiac injury.
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Affiliation(s)
- Zhiqiang Lin
- Masonic Medical Research Institute, 2150 Bleecker Street, Utica, NY, 13501, USA
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Deng J, Yan F, Tian J, Qiao A, Yan D. Potential clinical biomarkers and perspectives in diabetic cardiomyopathy. Diabetol Metab Syndr 2023; 15:35. [PMID: 36871006 PMCID: PMC9985231 DOI: 10.1186/s13098-023-00998-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Accepted: 02/15/2023] [Indexed: 03/06/2023] Open
Abstract
Diabetic cardiomyopathy (DCM) is a serious cardiovascular complication and the leading cause of death in diabetic patients. Patients typically do not experience any symptoms and have normal systolic and diastolic cardiac functions in the early stages of DCM. Because the majority of cardiac tissue has already been destroyed by the time DCM is detected, research must be conducted on biomarkers for early DCM, early diagnosis of DCM patients, and early symptomatic management to minimize mortality rates among DCM patients. Most of the existing implemented clinical markers are not very specific for DCM, especially in the early stages of DCM. Recent studies have shown that a number of new novel markers, such as galactin-3 (Gal-3), adiponectin (APN), and irisin, have significant changes in the clinical course of the various stages of DCM, suggesting that we may have a positive effect on the identification of DCM. As a summary of the current state of knowledge regarding DCM biomarkers, this review aims to inspire new ideas for identifying clinical markers and related pathophysiologic mechanisms that could be used in the early diagnosis and treatment of DCM.
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Affiliation(s)
- Jianxin Deng
- Department of Endocrinology, Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Health Science Center of Shenzhen University, Shenzhen Clinical Research Center for Metabolic Diseases, No. 3002, Sungang West Road, Futian District, Shenzhen, 518035, Guangdong Province, China
| | - Fang Yan
- Geriatric Diseases Institute of Chengdu, Center for Medicine Research and Translation, Chengdu Fifth People's Hospital, Chengdu, 611137, Sichuan Province, China
| | - Jinglun Tian
- Department of Geriatrics, the Traditional Chinese Medicine Hospital of Wenjiang District, Chengdu, 611130, China
| | - Aijun Qiao
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528400, Guangdong Province, China.
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, China.
| | - Dewen Yan
- Department of Endocrinology, Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Health Science Center of Shenzhen University, Shenzhen Clinical Research Center for Metabolic Diseases, No. 3002, Sungang West Road, Futian District, Shenzhen, 518035, Guangdong Province, China.
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Sharma K, Rani V. Organosulfur Compounds in Aged Garlic Extract Ameliorate Glucose Induced Diabetic Cardiomyopathy by Attenuating Oxidative Stress, Cardiac Fibrosis, and Cardiac Apoptosis. Cardiovasc Hematol Agents Med Chem 2023; 22:66-82. [PMID: 36825728 DOI: 10.2174/1871525721666230223145218] [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: 07/26/2022] [Revised: 12/26/2022] [Accepted: 12/26/2022] [Indexed: 02/25/2023]
Abstract
BACKGROUND Diabetic cardiomyopathy has emerged as a major cause of cardiac fibrosis, hypertrophy, diastolic dysfunction, and heart failure due to uncontrolled glucose metabolism in patients with diabetes mellitus. However, there is still no consensus on the optimal treatment to prevent or treat the cardiac burden associated with diabetes, which urges the development of dual antidiabetic and cardioprotective cardiac therapy based on natural products. This study investigates the cardiotoxic profile of glucose and the efficacy of AGE against glucose-induced cardiotoxicity in H9c2 cardiomyocytes. METHODS The cellular metabolic activity of H9c2 cardiomyocytes under increasing glucose concentration and the therapeutic efficacy of AGE were investigated using the MTT cell cytotoxicity assay. The in vitro model was established in six groups known as 1. control, 2. cells treated with 25 μM glucose, 3. 100 μM glucose, 4. 25 μM glucose +35 μM AGE, 5. 100 μM glucose + 35 μM AGE, and 6. 35 μM AGE. Morphological and nuclear analyses were performed using Giemsa, HE, DAPI, and PI, respectively, whereas cell death was simultaneously assessed using the trypan blue assay. The antioxidant potential of AGE was evaluated by DCFH-DA assay, NO, and H202 scavenging assay. The activities of the antioxidant enzymes catalase and superoxide dismutase were also investigated. The antiglycative potential of AGE was examined by antiglycation assays, amylase zymography, and SDS PAGE. These results were then validated by in silico molecular docking and qRTPCR. RESULTS Hyperglycemia significantly reduced cellular metabolic activity of H9c2 cardiomyocytes, and AGE was found to preserve cell viability approximately 2-fold by attenuating oxidative, fibrosis, and apoptotic signaling molecules. In silico and qRTPCR studies confirmed that organosulfur compounds target TNF-α, MAPK, TGF-β, MMP-7, and caspase-9 signaling molecules to ameliorate glucose-induced cardiotoxicity. CONCLUSION AGE was found to be an antidiabetic and cardioprotective natural product with exceptional therapeutic potential for use as a novel herb-drug therapy in the treatment of diabetic cardiomyopathy in future therapies.
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Affiliation(s)
- Kumkum Sharma
- Department of Biotechnology, Transcriptome Lab, Centre for Emerging Diseases, Jaypee Institute of Information Technology, Noida, Sector- 62, Uttar Pradesh, India
| | - Vibha Rani
- Department of Biotechnology, Transcriptome Lab, Centre for Emerging Diseases, Jaypee Institute of Information Technology, Noida, Sector- 62, Uttar Pradesh, India
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LncRNA H19 inhibits ER stress induced apoptosis and improves diabetic cardiomyopathy by regulating PI3K/AKT/mTOR axis. Aging (Albany NY) 2022; 14:6809-6828. [PMID: 36044268 PMCID: PMC9467416 DOI: 10.18632/aging.204256] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Accepted: 08/17/2022] [Indexed: 02/06/2023]
Abstract
Objective: Extensive studies have shown that ERS may be implicated in the pathogenesis of DCM. We explored the therapeutic effects of lncRNAH19 on DCM and its effect on ERS-associated cardiomyocyte apoptosis. Methods: C57/BL-6j mice were randomly divided into 3 groups: non-DM group (controls), DM group (DCM), and lncRNAH19 overexpression group (DCM+H19 group). The effect of H19 on cardiac function was detected. The effect of H19 on cardiomyocyte apoptosis and cardiac fibrosis in DM was examined. Differentially expressed genes (DEGs) and activated pathways were examined by bioinformatics analysis. STRING database was applied to construct a PPI network using Cytoscape software. The expression of p-PERK, p-IRE1, ATF6, CHOP, cleaved caspase-3, -9, -12 and BAX proteins in cardiac tissue was used to determine the ERS-associated apoptotic indicators. We established the HG-stimulated inflammatory cell model. The expression of p-PERK and CHOP in HL-1 cells following HG was determined by immunofluorescence labeling. The effects of H19 on ERS and PI3K/AKT/mTOR pathway were also detected. Results: H19 improved left ventricular dysfunction in DM. H19 could reduce cardiomyocytes apoptosis and improve fibrosis in vivo. H19 could reduce the expression of p-PERK, p-IRE1α, ATF6, CHOP, cleaved caspase-3, cleaved caspase-9, cleaved caspase-12, and BAX proteins in cardiac tissues. Furthermore, H19 repressed oxidative stress, ERS and apoptosis in vitro. Moreover, the effect of H19 on ERS-associated apoptosis might be rescued by LY294002 (the specific inhibitor for PI3K and AKT). Conclusion: H19 attenuates DCM in DM and ROS, ERS-induced cardiomyocyte apoptosis, which is associated with the activation of PI3K/AKT/mTOR signaling pathway.
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da Purificação NRC, Garcia VB, Frez FCV, Sehaber CC, Lima KRDA, de Oliveira Lima MF, de Carvalho Vasconcelos R, de Araujo AA, de Araújo Júnior RF, Lacchini S, de Oliveira F, Perles JVCM, Zanoni JN, de Sousa Lopes MLD, Clebis NK. Combined use of systemic quercetin, glutamine and alpha-tocopherol attenuates myocardial fibrosis in diabetic rats. Biomed Pharmacother 2022; 151:113131. [PMID: 35643067 DOI: 10.1016/j.biopha.2022.113131] [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: 03/23/2022] [Revised: 05/11/2022] [Accepted: 05/13/2022] [Indexed: 11/02/2022] Open
Abstract
This study aimed to analyze the effects of the quercetin (100 mg/kg), 1% glutamine and 1% α-tocopherol antioxidants in the myocardium of rats with streptozotocin-induced diabetes mellitus. Twenty male rats were subdivided into four groups (n = 5): N (normoglycemic); D (diabetic); NT (normoglycemic treated with antioxidants); and DT (diabetic treated with antioxidants) treated for 60 days. Clinical parameters, oxidative stress markers, inflammatory cytokines, myocardial collagen fibers and immunoexpression of superoxide dismutase 1 (SOD-1), glutathione peroxidase-1 (GPx-1), interleukin-1β (IL-1-β), transforming growth factor-beta (TGF-β), and fibroblast growth factor-2 (FGF-2) were evaluated. Results showed reduced body weight, hyperphagia, polydipsia and hyperglycemic state in groups D and DT. The levels of glutathione (GSH) were higher in NT and DT compared to N (p < 0.01) and D (p < 0.001) groups, respectively. Greater GSH levels were found in DT when compared to N animals (p < 0.001). In DT, there was an increase in IL-10 in relation to N, D and NT (p < 0.05), while GPx-1 expression was similar to N and lower compared to D (p < 0.001). TGF-β expression in DT was greater than N (p < 0.001) group, whereas FGF-2 in DT was higher than in the other groups (p < 0.001). A significant reduction in collagen fibers (type I) was found in DT compared to D (p < 0.05). The associated administration of quercetin, glutamine and α-tocopherol increased the levels of circulating interleukin-10 (IL-10) and GSH, and reduced the number of type I collagen fibers. Combined use of systemic quercetin, glutamine and alpha-tocopherol attenuates myocardial fibrosis in diabetic rats.
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Affiliation(s)
| | | | | | | | - Kaio Ramon De Aguiar Lima
- Postgraduate Program in Functional & Structural Biology, Departament of Morphology, UFRN, Natal, RN, Brazil
| | | | | | - Aurigena Antunes de Araujo
- Postgraduate Program in Pharmaceutical Sciences, Postgraduate Program in Dental Sciences, Department of Pharmacology and Biophysical, UFRN, Natal, RN, Brazil.
| | - Raimundo Fernandes de Araújo Júnior
- Postgraduate Program in Health Sciences, Postgraduate Program in Functional & Structural Biology, Departament of Morphology, UFRN, Natal, RN, Brazil
| | - Silvia Lacchini
- Postgraduate Program in Morphology Science, Departamento of Anatomy, São Paulo University, São Paulo, SP, Brazil
| | - Flávia de Oliveira
- Departament of Biocience, Federal University of São Paulo (UNIFESP), Santos, SP, Brazil
| | | | | | | | - Naianne Kelly Clebis
- Postgraduate Program in Functional & Structural Biology, Departament of Morphology, UFRN, Natal, RN, Brazil
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14
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Hao M, Deng J, Huang X, Li H, Ou H, Cai X, She J, Liu X, Chen L, Chen S, Liu W, Yan D. Metabonomic Characteristics of Myocardial Diastolic Dysfunction in Type 2 Diabetic Cardiomyopathy Patients. Front Physiol 2022; 13:863347. [PMID: 35651872 PMCID: PMC9150260 DOI: 10.3389/fphys.2022.863347] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Accepted: 03/28/2022] [Indexed: 12/26/2022] Open
Abstract
Diabetic cardiomyopathy (DCM) is one of the most essential cardiovascular complications in diabetic patients associated with glucose and lipid metabolism disorder, fibrosis, oxidative stress, and inflammation in cardiomyocytes. Despite increasing research on the molecular pathogenesis of DCM, it is still unclear whether metabolic pathways and alterations are probably involved in the development of DCM. This study aims to characterize the metabolites of DCM and to identify the relationship between metabolites and their biological processes or biological states through untargeted metabolic profiling. UPLC-MS/MS was applied to profile plasma metabolites from 78 patients with diabetes (39 diabetes with DCM and 39 diabetes without DCM as controls). A total of 2,806 biochemical were detected. Compared to those of DM patients, 78 differential metabolites in the positive-ion mode were identified in DCM patients, including 33 up-regulated and 45 down-regulated metabolites; however, there were only six differential metabolites identified in the negative mode including four up-regulated and two down-regulated metabolites. Alterations of several serum metabolites, including lipids and lipid-like molecules, organic acids and derivatives, organic oxygen compounds, benzenoids, phenylpropanoids and polyketides, and organoheterocyclic compounds, were associated with the development of DCM. KEGG enrichment analysis showed that there were three signaling pathways (metabolic pathways, porphyrin, chlorophyll metabolism, and lysine degradation) that were changed in both negative- and positive-ion modes. Our results demonstrated that differential metabolites and lipids have specific effects on DCM. These results expanded our understanding of the metabolic characteristics of DCM and may provide a clue in the future investigation of reducing the incidence of DCM. Furthermore, the metabolites identified here may provide clues for clinical management and the development of effective drugs.
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Affiliation(s)
- Mingyu Hao
- Department of Endocrinology, Shenzhen Clinical Research Center for Metabolic Diseases, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Health Science Center of Shenzhen University, Shenzhen, China
- Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Jianxin Deng
- Department of Endocrinology, Shenzhen Clinical Research Center for Metabolic Diseases, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Health Science Center of Shenzhen University, Shenzhen, China
| | - Xiaohong Huang
- Department of Endocrinology, Shenzhen Clinical Research Center for Metabolic Diseases, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Health Science Center of Shenzhen University, Shenzhen, China
| | - Haiyan Li
- Department of Endocrinology, Shenzhen Clinical Research Center for Metabolic Diseases, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Health Science Center of Shenzhen University, Shenzhen, China
| | - Huiting Ou
- Department of Endocrinology, Shenzhen Clinical Research Center for Metabolic Diseases, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Health Science Center of Shenzhen University, Shenzhen, China
| | - Xiangsheng Cai
- Institute of Translational Medicine, University of Chinese Academy of Science-Shenzhen Hospital, Shenzhen, China
| | - Jiajie She
- Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- The First Affiliated Hospital of Shenzhen University, Reproductive Medicine Centre, Shenzhen Second People’s Hospital, Shenzhen, China
| | - Xueting Liu
- Department of Endocrinology, Shenzhen Clinical Research Center for Metabolic Diseases, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Health Science Center of Shenzhen University, Shenzhen, China
| | - Ling Chen
- Department of Endocrinology, Shenzhen Clinical Research Center for Metabolic Diseases, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Health Science Center of Shenzhen University, Shenzhen, China
| | - Shujuan Chen
- Department of Endocrinology, Shenzhen Clinical Research Center for Metabolic Diseases, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Health Science Center of Shenzhen University, Shenzhen, China
| | - Wenlan Liu
- Department of Neurosurgery, Shenzhen Key Laboratory of Neurosurgery, Shenzhen Second People’s Hospital, Shenzhen University First Affiliated Hospital, Shenzhen, China
| | - Dewen Yan
- Department of Endocrinology, Shenzhen Clinical Research Center for Metabolic Diseases, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Health Science Center of Shenzhen University, Shenzhen, China
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15
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Zhu H, Wang X, Meng X, Kong Y, Li Y, Yang C, Guo Y, Wang X, Yang H, Liu Z, Wang F. Selenium Supplementation Improved Cardiac Functions by Suppressing DNMT2-Mediated GPX1 Promoter DNA Methylation in AGE-Induced Heart Failure. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:5402997. [PMID: 35432721 PMCID: PMC9007686 DOI: 10.1155/2022/5402997] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 03/03/2022] [Indexed: 12/14/2022]
Abstract
Objective Advanced glycation end products (AGEs) are featured metabolites associated with diabetic cardiomyopathy which is characterized by heart failure caused by myocyte apoptosis. Selenium was proved cardioprotective. This study was aimed at investigating the therapeutic effects and underlying mechanisms of selenium supplementation on AGE-induced heart failure. Methods Rats and primary myocytes were exposed to AGEs. Selenium supplementation was administrated. Cardiac functions and myocyte apoptosis were evaluated. Oxidative stress was assessed by total antioxidant capacity (TAC), reactive oxygen species (ROS) generation, and GPX activity. Expression levels of DNA methyltransferases (DNMTs) and glutathione peroxidase 1 (GPX1) were evaluated. DNA methylation of the GPX1 promoter was analyzed. Results AGE exposure elevated intracellular ROS generation, induced myocyte apoptosis, and impaired cardiac functions. AGE exposure increased DNMT1 and DNMT2 expression, leading to the reduction of GPX1 expression and activity in the heart. Selenium supplementation decreased DNMT2 expression, recovered GPX1 expression and activity, and alleviated intracellular ROS generation and myocyte apoptosis, resulting in cardiac function recovery. DNA methylation analysis in primary myocytes indicated that selenium supplementation or DNMT inhibitor AZA treatment reduced DNA methylation of the GPX1 gene promoter. Selenium supplementation and AZA administration showed synergic inhibitory effect on GPX1 gene promoter methylation. Conclusions Selenium supplementation showed cardioprotective effects on AGE-induced heart failure by suppressing ROS-mediated myocyte apoptosis. Selenium supplementation suppressed ROS generation by increasing GPX1 expression via inhibiting DNMT2-induced GPX1 gene promoter DNA methylation in myocytes exposed to AGEs.
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Affiliation(s)
- Huolan Zhu
- Department of Geriatrics, Shaanxi Provincial Clinical Research Center for Geriatric Medicine, Shaanxi Provincial People's Hospital, Xi'an, China
- Department of Cardiology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Xiang Wang
- Department of Cardiology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
- Graduate School, Peking Union Medical College, Chinese Academy of Medical Science, Beijing, China
| | - Xuyang Meng
- Department of Cardiology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
- Graduate School, Peking Union Medical College, Chinese Academy of Medical Science, Beijing, China
| | - Yiya Kong
- Department of Cardiology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
- Graduate School, Peking Union Medical College, Chinese Academy of Medical Science, Beijing, China
| | - Yi Li
- Department of Cardiology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Chenguang Yang
- Department of Cardiology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Ying Guo
- Department of Cardiology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Xiqiang Wang
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, China
- Cardiovascular Research Center, Shaanxi Provincial People's Hospital, Xi'an, China
| | - Haini Yang
- Cardiovascular Research Center, Shaanxi Provincial People's Hospital, Xi'an, China
| | - Zhongwei Liu
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, China
- Cardiovascular Research Center, Shaanxi Provincial People's Hospital, Xi'an, China
| | - Fang Wang
- Department of Cardiology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
- Graduate School, Peking Union Medical College, Chinese Academy of Medical Science, Beijing, China
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16
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Ho KL, Karwi QG, Connolly D, Pherwani S, Ketema EB, Ussher JR, Lopaschuk GD. Metabolic, structural and biochemical changes in diabetes and the development of heart failure. Diabetologia 2022; 65:411-423. [PMID: 34994805 DOI: 10.1007/s00125-021-05637-7] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Accepted: 10/28/2021] [Indexed: 12/21/2022]
Abstract
Diabetes contributes to the development of heart failure through various metabolic, structural and biochemical changes. The presence of diabetes increases the risk for the development of cardiovascular disease (CVD), and since the introduction of cardiovascular outcome trials to test diabetic drugs, the importance of improving our understanding of the mechanisms by which diabetes increases the risk for heart failure has come under the spotlight. In addition to the coronary vasculature changes that predispose individuals with diabetes to coronary artery disease, diabetes can also lead to cardiac dysfunction independent of ischaemic heart disease. The hyperlipidaemic, hyperglycaemic and insulin resistant state of diabetes contributes to a perturbed energy metabolic milieu, whereby the heart increases its reliance on fatty acids and decreases glucose oxidative rates. In addition to changes in cardiac energy metabolism, extracellular matrix remodelling contributes to the development of cardiac fibrosis, and impairments in calcium handling result in cardiac contractile dysfunction. Lipotoxicity and glucotoxicity also contribute to impairments in vascular function, cardiac contractility, calcium signalling, oxidative stress, cardiac efficiency and lipoapoptosis. Lastly, changes in protein acetylation, protein methylation and DNA methylation contribute to a myriad of gene expression and protein activity changes. Altogether, these changes lead to decreased cardiac efficiency, increased vulnerability to an ischaemic insult and increased risk for the development of heart failure. This review explores the above mechanisms and the way in which they contribute to cardiac dysfunction in diabetes.
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Affiliation(s)
- Kim L Ho
- Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada
| | - Qutuba G Karwi
- Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada
| | - David Connolly
- Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada
| | - Simran Pherwani
- Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada
| | - Ezra B Ketema
- Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada
| | - John R Ussher
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada
| | - Gary D Lopaschuk
- Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
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17
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Wenzl FA, Ambrosini S, Mohammed SA, Kraler S, Lüscher TF, Costantino S, Paneni F. Inflammation in Metabolic Cardiomyopathy. Front Cardiovasc Med 2021; 8:742178. [PMID: 34671656 PMCID: PMC8520939 DOI: 10.3389/fcvm.2021.742178] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Accepted: 08/31/2021] [Indexed: 12/24/2022] Open
Abstract
Overlapping pandemics of lifestyle-related diseases pose a substantial threat to cardiovascular health. Apart from coronary artery disease, metabolic disturbances linked to obesity, insulin resistance and diabetes directly compromise myocardial structure and function through independent and shared mechanisms heavily involving inflammatory signals. Accumulating evidence indicates that metabolic dysregulation causes systemic inflammation, which in turn aggravates cardiovascular disease. Indeed, elevated systemic levels of pro-inflammatory cytokines and metabolic substrates induce an inflammatory state in different cardiac cells and lead to subcellular alterations thereby promoting maladaptive myocardial remodeling. At the cellular level, inflammation-induced oxidative stress, mitochondrial dysfunction, impaired calcium handling, and lipotoxicity contribute to cardiomyocyte hypertrophy and dysfunction, extracellular matrix accumulation and microvascular disease. In cardiometabolic patients, myocardial inflammation is maintained by innate immune cell activation mediated by pattern recognition receptors such as Toll-like receptor 4 (TLR4) and downstream activation of the NLRP3 inflammasome and NF-κB-dependent pathways. Chronic low-grade inflammation progressively alters metabolic processes in the heart, leading to a metabolic cardiomyopathy (MC) phenotype and eventually to heart failure with preserved ejection fraction (HFpEF). In accordance with preclinical data, observational studies consistently showed increased inflammatory markers and cardiometabolic features in patients with HFpEF. Future treatment approaches of MC may target inflammatory mediators as they are closely intertwined with cardiac nutrient metabolism. Here, we review current evidence on inflammatory processes involved in the development of MC and provide an overview of nutrient and cytokine-driven pro-inflammatory effects stratified by cell type.
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Affiliation(s)
- Florian A Wenzl
- Center for Molecular Cardiology, University of Zurich, Zurich, Switzerland
| | - Samuele Ambrosini
- Center for Molecular Cardiology, University of Zurich, Zurich, Switzerland
| | - Shafeeq A Mohammed
- Center for Molecular Cardiology, University of Zurich, Zurich, Switzerland
| | - Simon Kraler
- Center for Molecular Cardiology, University of Zurich, Zurich, Switzerland
| | - Thomas F Lüscher
- Center for Molecular Cardiology, University of Zurich, Zurich, Switzerland.,Royal Brompton and Harefield Hospitals and Imperial College, London, United Kingdom
| | - Sarah Costantino
- Center for Molecular Cardiology, University of Zurich, Zurich, Switzerland
| | - Francesco Paneni
- Center for Molecular Cardiology, University of Zurich, Zurich, Switzerland.,University Heart Center, Cardiology, University Hospital Zurich, Zurich, Switzerland.,Department of Research and Education, University Hospital Zurich, Zurich, Switzerland
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18
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Kaur N, Guan Y, Raja R, Ruiz-Velasco A, Liu W. Mechanisms and Therapeutic Prospects of Diabetic Cardiomyopathy Through the Inflammatory Response. Front Physiol 2021; 12:694864. [PMID: 34234695 PMCID: PMC8257042 DOI: 10.3389/fphys.2021.694864] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Accepted: 05/10/2021] [Indexed: 12/14/2022] Open
Abstract
The incidence of heart failure (HF) continues to increase rapidly in patients with diabetes. It is marked by myocardial remodeling, including fibrosis, hypertrophy, and cell death, leading to diastolic dysfunction with or without systolic dysfunction. Diabetic cardiomyopathy (DCM) is a distinct myocardial disease in the absence of coronary artery disease. DCM is partially induced by chronic systemic inflammation, underpinned by a hostile environment due to hyperglycemia, hyperlipidemia, hyperinsulinemia, and insulin resistance. The detrimental role of leukocytes, cytokines, and chemokines is evident in the diabetic heart, yet the precise role of inflammation as a cause or consequence of DCM remains incompletely understood. Here, we provide a concise review of the inflammatory signaling mechanisms contributing to the clinical complications of diabetes-associated HF. Overall, the impact of inflammation on the onset and development of DCM suggests the potential benefits of targeting inflammatory cascades to prevent DCM. This review is tailored to outline the known effects of the current anti-diabetic drugs, anti-inflammatory therapies, and natural compounds on inflammation, which mitigate HF progression in diabetic populations.
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Affiliation(s)
| | | | | | | | - Wei Liu
- Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine, and Health, The University of Manchester, Manchester, United Kingdom
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19
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Prashanth G, Vastrad B, Tengli A, Vastrad C, Kotturshetti I. Investigation of candidate genes and mechanisms underlying obesity associated type 2 diabetes mellitus using bioinformatics analysis and screening of small drug molecules. BMC Endocr Disord 2021; 21:80. [PMID: 33902539 PMCID: PMC8074411 DOI: 10.1186/s12902-021-00718-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Accepted: 03/02/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Obesity associated type 2 diabetes mellitus is a metabolic disorder ; however, the etiology of obesity associated type 2 diabetes mellitus remains largely unknown. There is an urgent need to further broaden the understanding of the molecular mechanism associated in obesity associated type 2 diabetes mellitus. METHODS To screen the differentially expressed genes (DEGs) that might play essential roles in obesity associated type 2 diabetes mellitus, the publicly available expression profiling by high throughput sequencing data (GSE143319) was downloaded and screened for DEGs. Then, Gene Ontology (GO) and REACTOME pathway enrichment analysis were performed. The protein - protein interaction network, miRNA - target genes regulatory network and TF-target gene regulatory network were constructed and analyzed for identification of hub and target genes. The hub genes were validated by receiver operating characteristic (ROC) curve analysis and RT- PCR analysis. Finally, a molecular docking study was performed on over expressed proteins to predict the target small drug molecules. RESULTS A total of 820 DEGs were identified between healthy obese and metabolically unhealthy obese, among 409 up regulated and 411 down regulated genes. The GO enrichment analysis results showed that these DEGs were significantly enriched in ion transmembrane transport, intrinsic component of plasma membrane, transferase activity, transferring phosphorus-containing groups, cell adhesion, integral component of plasma membrane and signaling receptor binding, whereas, the REACTOME pathway enrichment analysis results showed that these DEGs were significantly enriched in integration of energy metabolism and extracellular matrix organization. The hub genes CEBPD, TP73, ESR2, TAB1, MAP 3K5, FN1, UBD, RUNX1, PIK3R2 and TNF, which might play an essential role in obesity associated type 2 diabetes mellitus was further screened. CONCLUSIONS The present study could deepen the understanding of the molecular mechanism of obesity associated type 2 diabetes mellitus, which could be useful in developing therapeutic targets for obesity associated type 2 diabetes mellitus.
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Affiliation(s)
- G Prashanth
- Department of General Medicine, Basaveshwara Medical College, Chitradurga, Karnataka, 577501, India
| | - Basavaraj Vastrad
- Department of Biochemistry, Basaveshwar College of Pharmacy, Gadag, Karnataka, 582103, India
| | - Anandkumar Tengli
- Department of Pharmaceutical Chemistry, JSS College of Pharmacy, Mysuru and JSS Academy of Higher Education & Research, Mysuru, Karnataka, 570015, India
| | - Chanabasayya Vastrad
- Biostatistics and Bioinformatics, Chanabasava Nilaya, Bharthinagar, Dharwad, Karnataka, 580001, India.
| | - Iranna Kotturshetti
- Department of Ayurveda, Rajiv Gandhi Education Society`s Ayurvedic Medical College, Ron, Karnataka, 582209, India
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20
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Karwi QG, Ho KL, Pherwani S, Ketema EB, Sun QY, Lopaschuk GD. Concurrent diabetes and heart failure: interplay and novel therapeutic approaches. Cardiovasc Res 2021; 118:686-715. [PMID: 33783483 DOI: 10.1093/cvr/cvab120] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 03/29/2021] [Indexed: 12/12/2022] Open
Abstract
Diabetes mellitus increases the risk of developing heart failure, and the co-existence of both diseases worsens cardiovascular outcomes, hospitalization and the progression of heart failure. Despite current advancements on therapeutic strategies to manage hyperglycemia, the likelihood of developing diabetes-induced heart failure is still significant, especially with the accelerating global prevalence of diabetes and an ageing population. This raises the likelihood of other contributing mechanisms beyond hyperglycemia in predisposing diabetic patients to cardiovascular disease risk. There has been considerable interest in understanding the alterations in cardiac structure and function in the diabetic patients, collectively termed as "diabetic cardiomyopathy". However, the factors that contribute to the development of diabetic cardiomyopathies is not fully understood. This review summarizes the main characteristics of diabetic cardiomyopathies, and the basic mechanisms that contribute to its occurrence. This includes perturbations in insulin resistance, fuel preference, reactive oxygen species generation, inflammation, cell death pathways, neurohormonal mechanisms, advanced glycated end-products accumulation, lipotoxicity, glucotoxicity, and posttranslational modifications in the heart of the diabetic. This review also discusses the impact of antihyperglycemic therapies on the development of heart failure, as well as how current heart failure therapies influence glycemic control in diabetic patients. We also highlight the current knowledge gaps in understanding how diabetes induces heart failure.
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Affiliation(s)
- Qutuba G Karwi
- Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada
| | - Kim L Ho
- Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada
| | - Simran Pherwani
- Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada
| | - Ezra B Ketema
- Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada
| | - Qiu Yu Sun
- Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada
| | - Gary D Lopaschuk
- Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada
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21
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Tian JH, Wu Q, He YX, Shen QY, Rekep M, Zhang GP, Luo JD, Xue Q, Liu YH. Zonisamide, an antiepileptic drug, alleviates diabetic cardiomyopathy by inhibiting endoplasmic reticulum stress. Acta Pharmacol Sin 2021; 42:393-403. [PMID: 32647341 PMCID: PMC8026994 DOI: 10.1038/s41401-020-0461-z] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Accepted: 06/11/2020] [Indexed: 02/06/2023]
Abstract
Endoplasmic reticulum stress (ER stress) plays a key role in the development of cardiac hypertrophy and diabetic cardiomyopathy (DCM). Zonisamide (ZNS) was originally developed as an antiepileptic drug. Studies have shown that ZNS suppresses ER stress-induced neuronal cell damage in the experimental models of Parkinson's disease. Herein, we investigated whether ZNS improved DCM by attenuating ER stress-induced apoptosis. C57BL/6J mice were fed with high-fat diet (HFD) and intraperitoneally injected with low-dose streptozotocin (STZ) to induce type 2 diabetes mellitus (T2DM), and then treated with ZNS (40 mg·kg-1·d-1, i.g.) for 16 weeks. We showed that ZNS administration slightly ameliorated the blood glucose levels, but significantly alleviated diabetes-induced cardiac dysfunction and hypertrophy. Furthermore, ZNS administration significantly inhibited the Bax and caspase-3 activity, upregulated Bcl-2 activity, and decreased the proportion of TUNEL-positive cells in heart tissues. We analyzed the hallmarks of ER stress in heart tissues, and revealed that ZNS administration significantly decreased the protein levels of GRP78, XBP-1s, ATF6, PERK, ATF4, and CHOP, and elevated Hrd1 protein. In high glucose (HG)-treated primary cardiomyocytes, application of ZNS (3 μM) significantly alleviated HG-induced cardiomyocyte hypertrophy and apoptosis. ZNS application also suppressed activated ER stress in HG-treated cardiomyocytes. Moreover, preapplication of the specific ER stress inducer tunicamycin (10 ng/mL) eliminated the protective effects of ZNS against HG-induced cardiac hypertrophy and ER stress-mediated apoptosis. Our findings suggest that ZNS improves the cardiac diastolic function in diabetic mice and prevents T2DM-induced cardiac hypertrophy by attenuating ER stress-mediated apoptosis.
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Affiliation(s)
- Jia-Hui Tian
- Department of Pharmacology, Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China
| | - Qian Wu
- Department of Pharmacology, Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China
| | - Yong-Xiang He
- Department of Pharmacology, Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China
| | - Qi-Ying Shen
- Department of Pharmacology, Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China
| | - Mubarak Rekep
- Department of Pharmacology, Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China
| | - Gui-Ping Zhang
- Department of Pharmacology, Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China
| | - Jian-Dong Luo
- Department of Pharmacology, Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China
| | - Qin Xue
- Department of Pharmacology, Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China.
| | - Ying-Hua Liu
- Department of Pharmacology, Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China.
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22
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Endoplasmic reticulum stress and unfolded protein response in cardiovascular diseases. Nat Rev Cardiol 2021; 18:499-521. [PMID: 33619348 DOI: 10.1038/s41569-021-00511-w] [Citation(s) in RCA: 421] [Impact Index Per Article: 105.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/11/2021] [Indexed: 02/07/2023]
Abstract
Cardiovascular diseases (CVDs), such as ischaemic heart disease, cardiomyopathy, atherosclerosis, hypertension, stroke and heart failure, are among the leading causes of morbidity and mortality worldwide. Although specific CVDs and the associated cardiometabolic abnormalities have distinct pathophysiological and clinical manifestations, they often share common traits, including disruption of proteostasis resulting in accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER). ER proteostasis is governed by the unfolded protein response (UPR), a signalling pathway that adjusts the protein-folding capacity of the cell to sustain the cell's secretory function. When the adaptive UPR fails to preserve ER homeostasis, a maladaptive or terminal UPR is engaged, leading to the disruption of ER integrity and to apoptosis. ER stress functions as a double-edged sword, with long-term ER stress resulting in cellular defects causing disturbed cardiovascular function. In this Review, we discuss the distinct roles of the UPR and ER stress response as both causes and consequences of CVD. We also summarize the latest advances in our understanding of the importance of the UPR and ER stress in the pathogenesis of CVD and discuss potential therapeutic strategies aimed at restoring ER proteostasis in CVDs.
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23
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Kaur N, Raja R, Ruiz-Velasco A, Liu W. Cellular Protein Quality Control in Diabetic Cardiomyopathy: From Bench to Bedside. Front Cardiovasc Med 2020; 7:585309. [PMID: 33195472 PMCID: PMC7593653 DOI: 10.3389/fcvm.2020.585309] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Accepted: 09/09/2020] [Indexed: 12/14/2022] Open
Abstract
Heart failure is a serious comorbidity and the most common cause of mortality in diabetes patients. Diabetic cardiomyopathy (DCM) features impaired cellular structure and function, culminating in heart failure; however, there is a dearth of specific clinical therapy for treating DCM. Protein homeostasis is pivotal for the maintenance of cellular viability under physiological and pathological conditions, particularly in the irreplaceable cardiomyocytes; therefore, it is tightly regulated by a protein quality control (PQC) system. Three evolutionarily conserved molecular processes, the unfolded protein response (UPR), the ubiquitin-proteasome system (UPS), and autophagy, enhance protein turnover and preserve protein homeostasis by suppressing protein translation, degrading misfolded or unfolded proteins in cytosol or organelles, disposing of damaged and toxic proteins, recycling essential amino acids, and eliminating insoluble protein aggregates. In response to increased cellular protein demand under pathological insults, including the diabetic condition, a coordinated PQC system retains cardiac protein homeostasis and heart performance, on the contrary, inappropriate PQC function exaggerates cardiac proteotoxicity with subsequent heart dysfunction. Further investigation of the PQC mechanisms in diabetes propels a more comprehensive understanding of the molecular pathogenesis of DCM and opens new prospective treatment strategies for heart disease and heart failure in diabetes patients. In this review, the function and regulation of cardiac PQC machinery in diabetes mellitus, and the therapeutic potential for the diabetic heart are discussed.
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Affiliation(s)
- Namrita Kaur
- Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine, and Health, The University of Manchester, Manchester, United Kingdom
| | - Rida Raja
- Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine, and Health, The University of Manchester, Manchester, United Kingdom
| | - Andrea Ruiz-Velasco
- Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine, and Health, The University of Manchester, Manchester, United Kingdom
| | - Wei Liu
- Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine, and Health, The University of Manchester, Manchester, United Kingdom
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24
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Wang Q, Luo C, Lu G, Chen Z. Effect of adenosine monophosphate-activated protein kinase-p53-Krüppel-like factor 2a pathway in hyperglycemia-induced cardiac remodeling in adult zebrafish. J Diabetes Investig 2020; 12:320-333. [PMID: 32881390 PMCID: PMC7926222 DOI: 10.1111/jdi.13393] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Revised: 08/07/2020] [Accepted: 08/12/2020] [Indexed: 01/10/2023] Open
Abstract
Aims/Introduction Diabetic cardiomyopathy is a type of myocardial disease. It causes left ventricular hypertrophy, followed by diastolic and systolic dysfunction, eventually leading to congestive heart failure. However, the underlying mechanism still requires further elucidation. Materials and Methods A high‐glucose zebrafish model was constructed by administering streptozocin intraperitoneally to enhance the development of cardiomyopathy and then treated with adenosine monophosphate‐activated protein kinase (AMPK) activator. Cardiac structure and function, and protein and gene expression were then analyzed. Cardiomyocytes (CMs) culture in vitro using lentivirus were used for detection of AMPK, p53 and Krüppel‐like factor 2a (klf2a) gene expression. Results In the hyperglycemia group, electrocardiogram findings showed arrhythmia, echocardiography results showed heart enlargement and dysfunction, and many differences, such as increased apoptosis and myocardial fiber loss, were observed. The phospho‐AMPK and klf2a expression were downregulated, and p53 expression was upregulated. Activation of phospho‐AMPK reduced p53 and increased klf2a expression, alleviated apoptosis in CMs and improved cardiac function in the hyperglycemic zebrafish. In vitro knockdown system of AMPK, p53 and klf2a using lentivirus illustrated an increased p53 expression and decreased klf2a expression in CMs by inhibiting AMPK. Repression of p53 and upregulation of klf2a expression were observed, but no changes in the expression of AMPK and its phosphorylated type. Conclusions In the model of streptozocin‐induced hyperglycemia zebrafish, the reduction of phosphorylated AMPK increased p53, which led to KLF2a decrease to facilitate apoptosis of CMs, inducing the cardiac remodeling and cardiac dysfunction. These results can be reversed by AMPK activator, which means the AMPK–p53–klf2a pathway might be a potential target for diabetic cardiomyopathy intervention.
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Affiliation(s)
- Qiuyun Wang
- Department of Cardiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Chen Luo
- Department of Cardiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Guoping Lu
- Department of Cardiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Zhenyue Chen
- Department of Cardiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
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25
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Tan Y, Zhang Z, Zheng C, Wintergerst KA, Keller BB, Cai L. Mechanisms of diabetic cardiomyopathy and potential therapeutic strategies: preclinical and clinical evidence. Nat Rev Cardiol 2020; 17:585-607. [PMID: 32080423 PMCID: PMC7849055 DOI: 10.1038/s41569-020-0339-2] [Citation(s) in RCA: 474] [Impact Index Per Article: 94.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/16/2020] [Indexed: 02/07/2023]
Abstract
The pathogenesis and clinical features of diabetic cardiomyopathy have been well-studied in the past decade, but effective approaches to prevent and treat this disease are limited. Diabetic cardiomyopathy occurs as a result of the dysregulated glucose and lipid metabolism associated with diabetes mellitus, which leads to increased oxidative stress and the activation of multiple inflammatory pathways that mediate cellular and extracellular injury, pathological cardiac remodelling, and diastolic and systolic dysfunction. Preclinical studies in animal models of diabetes have identified multiple intracellular pathways involved in the pathogenesis of diabetic cardiomyopathy and potential cardioprotective strategies to prevent and treat the disease, including antifibrotic agents, anti-inflammatory agents and antioxidants. Some of these interventions have been tested in clinical trials and have shown favourable initial results. In this Review, we discuss the mechanisms underlying the development of diabetic cardiomyopathy and heart failure in type 1 and type 2 diabetes mellitus, and we summarize the evidence from preclinical and clinical studies that might provide guidance for the development of targeted strategies. We also highlight some of the novel pharmacological therapeutic strategies for the treatment and prevention of diabetic cardiomyopathy.
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Affiliation(s)
- Yi Tan
- Pediatric Research Institute, Department of Pediatrics, University of Louisville School of Medicine, Louisville, KY, USA.
- Wendy Novak Diabetes Center, University of Louisville, Norton Children's Hospital, Louisville, KY, USA.
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, USA.
| | - Zhiguo Zhang
- Department of Cardiology, The First Hospital of Jilin University, Changchun, China
| | - Chao Zheng
- The Second Affiliated Hospital Center of Chinese-American Research Institute for Diabetic Complications, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Kupper A Wintergerst
- Pediatric Research Institute, Department of Pediatrics, University of Louisville School of Medicine, Louisville, KY, USA
- Wendy Novak Diabetes Center, University of Louisville, Norton Children's Hospital, Louisville, KY, USA
- Division of Endocrinology, Department of Pediatrics, University of Louisville School of Medicine, Louisville, KY, USA
| | - Bradley B Keller
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, USA
- Kosair Charities Pediatric Heart Research Program, Cardiovascular Innovation Institute, University of Louisville, Louisville, KY, USA
| | - Lu Cai
- Pediatric Research Institute, Department of Pediatrics, University of Louisville School of Medicine, Louisville, KY, USA.
- Wendy Novak Diabetes Center, University of Louisville, Norton Children's Hospital, Louisville, KY, USA.
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, USA.
- Department of Radiation Oncology, University of Louisville School of Medicine, Louisville, KY, USA.
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26
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Chen X, Li H, Wang K, Liang X, Wang W, Hu X, Huang Z, Wang Y. Aerobic Exercise Ameliorates Myocardial Inflammation, Fibrosis and Apoptosis in High-Fat-Diet Rats by Inhibiting P2X7 Purinergic Receptors. Front Physiol 2019; 10:1286. [PMID: 31681001 PMCID: PMC6798156 DOI: 10.3389/fphys.2019.01286] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Accepted: 09/25/2019] [Indexed: 01/21/2023] Open
Abstract
Background High-fat-diet (HFD) is associated with chronic low-grade inflammation. P2X7 purinergic receptors (P2X7R) are key regulators of inflammasome activation. The benefits of exercise are partly attributed to its anti-inflammatory effect, but whether it regulates P2X7R expression to improve remodeling in cardiac myocytes treated by HFD is not completely clarified. Methods Three groups of Sprague-Dawley (SD) rats were studied: (1) control group (fed a normal chow diet), (2) HFD group, and (3) HFD+ exercise group. H9c2 myocytes were pretreated with or without A438079 (a P2X7R inhibitor) and then exposed to 200 μM palmitic acid (PA) for 24 h. The levels of mRNA and protein were measured by real-time PCR and Western blot, respectively. Masson staining and hematoxylin-eosin (HE) staining were used to identify remodeling of the heart. The concentration of IL-1β in serum or supernatants were measured by ELISA. Results In vivo, collagen deposition and the number of disordered cells significantly increased in the hearts of the HFD group compared to the control group. However, exercise markedly reversed these changes in the myocardium, and the same trends were observed in the expression of MMP9, collagen I and TGF-β. Notably, the expression of P2X7R, NLRP3, caspase-1 in the hearts, and serum IL-1β level were also greatly upregulated in the heart of the HFD diet rats, and all these changes were ameliorated in the HFD + EX group. As expected, exercise also reduced the number of TUNEL-positive cells, which was consistent with the caspase-3, Bax, and Bcl-2 results. Moreover, exercise reduced body weight and blood lipid concentrations in the HFD diet rats. In vitro, we observed that the hallmark of fibrosis, inflammation and apoptosis in H9c2 myocytes enhanced by PA, and the P2X7R inhibitor treatment significantly reduced the expression of the NLRP3, caspase-1, suppressed the secretion of IL-1β of H9c2 cells, inhibited collagen I, TGF-β, MMP9, Bax, caspase-3 levels and increased the expression of Bcl-2, compared with the PA group. In addition, a decrease of the number of TUNEL-positive cells used by A438079 further support that cardiomyocytes apoptosis could be inhibited. Conclusion Aerobic exercise reversed the cardiac remodeling via the reduction of inflammation, fibrosis and apoptosis in HFD rats, at least in part through inhibiting P2X7R expression in cardiomyocytes.
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Affiliation(s)
- Xudong Chen
- The Key Lab of Cardiovascular Disease of Wenzhou, Department of Cardiology, Wenzhou Medical University, Wenzhou, China.,Department of Cardiology, Ningbo Hangzhou Bay Hospital, Ningbo, China
| | - Haiyan Li
- Department of Rehabilitation, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Kangwei Wang
- The Key Lab of Cardiovascular Disease of Wenzhou, Department of Cardiology, Wenzhou Medical University, Wenzhou, China
| | - Xiaohe Liang
- The Key Lab of Cardiovascular Disease of Wenzhou, Department of Cardiology, Wenzhou Medical University, Wenzhou, China
| | - Weiqi Wang
- The Key Lab of Cardiovascular Disease of Wenzhou, Department of Cardiology, Wenzhou Medical University, Wenzhou, China
| | - Xiaokang Hu
- The Key Lab of Cardiovascular Disease of Wenzhou, Department of Cardiology, Wenzhou Medical University, Wenzhou, China
| | - Zhouqing Huang
- Department of Cardiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yonghua Wang
- Department of Physical Education, Wenzhou Medical University, Wenzhou, China
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27
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Andersohn A, Garcia MI, Fan Y, Thompson MC, Akimzhanov AM, Abdullahi A, Jeschke MG, Boehning D. Aggregated and Hyperstable Damage-Associated Molecular Patterns Are Released During ER Stress to Modulate Immune Function. Front Cell Dev Biol 2019; 7:198. [PMID: 31620439 PMCID: PMC6759876 DOI: 10.3389/fcell.2019.00198] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Accepted: 09/02/2019] [Indexed: 12/23/2022] Open
Abstract
Chronic ER stress occurs when protein misfolding in the Endoplasmic reticulum (ER) lumen remains unresolved despite activation of the unfolded protein response. We have shown that traumatic injury such as a severe burn leads to chronic ER stress in vivo leading to systemic inflammation which can last for more than a year. The mechanisms linking chronic ER stress to systemic inflammatory responses are not clear. Here we show that induction of chronic ER stress leads to the release of known and novel damage-associated molecular patterns (DAMPs). The secreted DAMPs are aggregated and markedly protease resistant. ER stress-derived DAMPs activate dendritic cells (DCs) which are then capable of polarizing naïve T cells. Our findings indicate that induction of chronic ER stress may lead to the release of hyperstable DAMPs into the circulation resulting in persistent systemic inflammation and adverse outcomes.
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Affiliation(s)
- Alexander Andersohn
- Department of Biochemistry and Molecular Biology, McGovern Medical School at UTHealth, Houston, TX, United States
| | - M Iveth Garcia
- Department of Biochemistry and Molecular Biology, McGovern Medical School at UTHealth, Houston, TX, United States
| | - Ying Fan
- Department of Biochemistry and Molecular Biology, McGovern Medical School at UTHealth, Houston, TX, United States
| | - Max C Thompson
- Department of Biochemistry and Molecular Biology, McGovern Medical School at UTHealth, Houston, TX, United States
| | - Askar M Akimzhanov
- Department of Biochemistry and Molecular Biology, McGovern Medical School at UTHealth, Houston, TX, United States
| | - Abdikarim Abdullahi
- Ross Tilley Burn Centre, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
| | - Marc G Jeschke
- Ross Tilley Burn Centre, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
| | - Darren Boehning
- Department of Biochemistry and Molecular Biology, McGovern Medical School at UTHealth, Houston, TX, United States.,Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ, United States
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28
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Wang Y, Li H, Li Y, Zhao Y, Xiong F, Liu Y, Xue H, Yang Z, Ni S, Sahil A, Che H, Wang L. Coriolus versicolor
alleviates diabetic cardiomyopathy by inhibiting cardiac fibrosis and NLRP3 inflammasome activation. Phytother Res 2019; 33:2737-2748. [PMID: 31338905 DOI: 10.1002/ptr.6448] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Revised: 06/06/2019] [Accepted: 07/01/2019] [Indexed: 12/13/2022]
Affiliation(s)
- Yueqiu Wang
- Department of EndocrinologyThe Second Affiliated Hospital of Harbin Medical University Harbin Heilongjiang Province 150001 China
| | - Hui Li
- Department of EndocrinologyThe Second Affiliated Hospital of Harbin Medical University Harbin Heilongjiang Province 150001 China
| | - Yang Li
- Department of EndocrinologyThe Second Affiliated Hospital of Harbin Medical University Harbin Heilongjiang Province 150001 China
| | - Yihan Zhao
- Department of EndocrinologyThe Second Affiliated Hospital of Harbin Medical University Harbin Heilongjiang Province 150001 China
| | - Fangfei Xiong
- Department of EndocrinologyThe Second Affiliated Hospital of Harbin Medical University Harbin Heilongjiang Province 150001 China
| | - Yining Liu
- Department of Pharmacology, College of PharmacyHarbin Medical University Harbin Heilongjiang Province 150001 China
| | - Hongru Xue
- Department of Pharmacology, College of PharmacyHarbin Medical University Harbin Heilongjiang Province 150001 China
| | - Zhenyu Yang
- Department of Pharmacology, College of PharmacyHarbin Medical University Harbin Heilongjiang Province 150001 China
| | - Sha Ni
- Department of Pharmacology, College of PharmacyHarbin Medical University Harbin Heilongjiang Province 150001 China
| | - Abbas Sahil
- Department of EndocrinologyThe Second Affiliated Hospital of Harbin Medical University Harbin Heilongjiang Province 150001 China
| | - Hui Che
- Department of EndocrinologyThe Second Affiliated Hospital of Harbin Medical University Harbin Heilongjiang Province 150001 China
- Institute of Chronic DiseaseHeilongjiang Academy of Medical Science Harbin Heilongjiang Province 150001 China
| | - Lihong Wang
- Department of EndocrinologyThe Second Affiliated Hospital of Harbin Medical University Harbin Heilongjiang Province 150001 China
- Institute of Chronic DiseaseHeilongjiang Academy of Medical Science Harbin Heilongjiang Province 150001 China
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29
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Li S, Liu R, Xue M, Qiao Y, Chen Y, Long G, Tian X, Hu Y, Zhou P, Dong X, Qi Z, Cui Y, Shen Y. Spleen tyrosine kinase‑induced JNK‑dependent NLRP3 activation is involved in diabetic cardiomyopathy. Int J Mol Med 2019; 43:2481-2490. [PMID: 30942391 DOI: 10.3892/ijmm.2019.4148] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Accepted: 03/20/2019] [Indexed: 11/05/2022] Open
Abstract
Diabetic cardiomyopathy (DCM) is a leading contributor to the increased morbidity and mortality rates associated with diabetes. Persistent inflammation has previously been reported to be involved in the pathogenesis of DCM. However, the exact underlying molecular mechanisms remain to be fully elucidated. In the present study, the role of spleen tyrosine kinase (Syk) and c‑Jun N‑terminal kinase (JNK) in NLR family pyrin domain‑containing 3 (NLRP3 inflammasome) activation in DCM were investigated in vivo and in vitro. Streptozotocin (65 mg/kg) was injected intraperitoneally into Sprague‑Dawley rats to induce a rat model of diabetes. Neonatal rat cardiomyocytes and H9c2 cells were cultured to detect the expression of JNK, NLRP3 and its associated downstream molecules, following treatment with Syk/JNK inhibitor or Syk/JNK‑small interfering (si)RNA in high glucose (HG) conditions. It was revealed that the protein and mRNA expression levels of phospho (p)‑Syk, p‑JNK, NLRP3 and its associated downstream molecules, including interleukin (IL)‑1β, were upregulated in vivo and in vitro. The JNK inhibitor significantly decreased the expression of NLRP3 and its downstream molecules in neonatal rat cardiomyocytes and H9c2 cells treated with HG. Furthermore, Syk‑siRNA and the Syk inhibitor markedly inhibited the HG‑induced activation of JNK, followed by the downregulation of NLRP3 and its downstream molecules at the mRNA and protein levels in cells. Therefore, it was demonstrated that the HG‑induced activation of NLRP3 was mediated by the activation of Syk/JNK, which subsequently increased the protein expression levels of mature IL‑1β, suggesting that the Syk/JNK/NLRP3 signaling pathway serves a critical role in the pathogenesis of DCM.
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Affiliation(s)
- Shengyu Li
- School of Medical Laboratory, Tianjin Medical University, Tianjin 300203, P.R. China
| | - Ruiqing Liu
- School of Medical Laboratory, Tianjin Medical University, Tianjin 300203, P.R. China
| | - Meiting Xue
- School of Medical Laboratory, Tianjin Medical University, Tianjin 300203, P.R. China
| | - Yingchun Qiao
- School of Medical Laboratory, Tianjin Medical University, Tianjin 300203, P.R. China
| | - Yufeng Chen
- School of Medical Laboratory, Tianjin Medical University, Tianjin 300203, P.R. China
| | - Guangfeng Long
- School of Medical Laboratory, Tianjin Medical University, Tianjin 300203, P.R. China
| | - Xixi Tian
- School of Medical Laboratory, Tianjin Medical University, Tianjin 300203, P.R. China
| | - Yahui Hu
- School of Medical Laboratory, Tianjin Medical University, Tianjin 300203, P.R. China
| | - Pengfei Zhou
- School of Medical Laboratory, Tianjin Medical University, Tianjin 300203, P.R. China
| | - Xiaohui Dong
- School of Medical Laboratory, Tianjin Medical University, Tianjin 300203, P.R. China
| | - Zhi Qi
- Department of Histology and Embryology, School of Medicine, Nankai University, Tianjin 300071, P.R. China
| | - Yujie Cui
- School of Medical Laboratory, Tianjin Medical University, Tianjin 300203, P.R. China
| | - Yanna Shen
- School of Medical Laboratory, Tianjin Medical University, Tianjin 300203, P.R. China
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宣 玲, 陈 斌, 郭 建, 康 品, 陶 敏, 高 琴, 唐 碧, 张 恒. [Effect of low-dose ethanol consumption on expression of nuclear factor-κB in diabetic rats with myocardial injury]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2018; 38:1255-1260. [PMID: 30377130 PMCID: PMC6744052 DOI: 10.3969/j.issn.1673-4254.2018.10.17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 01/13/2018] [Indexed: 06/08/2023]
Abstract
OBJECTIVE To investigate the effect of low-dose ethanol on the expression of nuclear factor-κB (NF-κB) in diabetic rats with myocardial injury. METHODS Rat models of diabetes were established by an intraperitoneal injection of 55 mg/kg streptozotocin (STZ). After successful modeling, the rats were given 2.5% ethanol (daily dose of 20 mg/kg) for 1 week, followed by 5% ethanol (daily dose of 39.45 mg/kg) for another 7 weeks. Normal rats without STZ injection and diabetic rats without ethanol treatment serve as the normal control and diabetic model groups, respectively. The ventricular function of the rats was determined using echocardiography. The plasma levels of interleukin-1 (IL-1) and IL-4 were detected in the rats, and the expressions of 4-HNE, NF-κB and IKK proteins in the left anterior myocardium was evaluated using immunohistochemistry or Western blotting; the ultrastructural changes of the myocardium were observed using transmission electron microscopy. RESULTS Compared with the normal control group, the diabetic rats showed significantly lowered systolic and diastolic functions of the left ventricle, increased plasma level of IL-1 and myocardial 4-HNE expression (P < 0.01), decreased plasma level of plasma IL-4 (P < 0.01), and increased myocardial expressions of NF-κB and IKK proteins (P < 0.01). Transmission electron microscopy revealed myofibrillar rupture, incomplete myofibrillar structure and mitochondrial damage in the cardiac myocytes in the diabetic rats. Compared with the diabetic rats, the rats with low-dose ethanol treatment exhibited improved systolic and diastolic functions of the left ventricle, milder myocardial myofibrillar and mitochondrial damages, and significantly lowered plasma IL-1 level and myocardial expressions of 4-HNE, NF-κB and IKK (P < 0.01), and increased plasma IL-4 level (P < 0.01). CONCLUSIONS NF-κB expression is increased in the myocardium of diabetic rats with myocardial injury, and low-dose ethanol consumption lowers myocardial expression of NF-κB in diabetic rats, suggesting the involvement of NF-κB signaling pathway in the protective effect of low-dose ethanol against myocardial injury in diabetes mellitus.
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Affiliation(s)
- 玲 宣
- 蚌埠医学院第一附属医院心血管内科，安徽 蚌埠 233000Department of Cardiovascular Medicine, First Affiliated Hospital of Bengbu Medical College, Bengbu Medical College, Bengbu 233000, China
| | - 斌 陈
- 蚌埠医学院第一附属医院心血管内科，安徽 蚌埠 233000Department of Cardiovascular Medicine, First Affiliated Hospital of Bengbu Medical College, Bengbu Medical College, Bengbu 233000, China
| | - 建路 郭
- 蚌埠医学院第一附属医院心血管内科，安徽 蚌埠 233000Department of Cardiovascular Medicine, First Affiliated Hospital of Bengbu Medical College, Bengbu Medical College, Bengbu 233000, China
| | - 品方 康
- 蚌埠医学院第一附属医院心血管内科，安徽 蚌埠 233000Department of Cardiovascular Medicine, First Affiliated Hospital of Bengbu Medical College, Bengbu Medical College, Bengbu 233000, China
| | - 敏 陶
- 蚌埠医学院第一附属医院心血管内科，安徽 蚌埠 233000Department of Cardiovascular Medicine, First Affiliated Hospital of Bengbu Medical College, Bengbu Medical College, Bengbu 233000, China
| | - 琴 高
- 蚌埠医学院生理学教研室，安徽 蚌埠 233000Department of Physiology, Bengbu Medical College, Bengbu 233000, China
| | - 碧 唐
- 蚌埠医学院第一附属医院心血管内科，安徽 蚌埠 233000Department of Cardiovascular Medicine, First Affiliated Hospital of Bengbu Medical College, Bengbu Medical College, Bengbu 233000, China
| | - 恒 张
- 蚌埠医学院第一附属医院心血管内科，安徽 蚌埠 233000Department of Cardiovascular Medicine, First Affiliated Hospital of Bengbu Medical College, Bengbu Medical College, Bengbu 233000, China
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Liu Z, Zheng S, Wang X, Qiu C, Guo Y. Novel ASK1 inhibitor AGI-1067 improves AGE-induced cardiac dysfunction by inhibiting MKKs/p38 MAPK and NF-κB apoptotic signaling. FEBS Open Bio 2018; 8:1445-1456. [PMID: 30186746 PMCID: PMC6120242 DOI: 10.1002/2211-5463.12499] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2018] [Revised: 06/14/2018] [Accepted: 06/25/2018] [Indexed: 12/28/2022] Open
Abstract
Heart failure has been identified as one of the clinical manifestations of diabetic cardiovascular complications. Excessive myocardium apoptosis characterizes cardiac dysfunctions, which are correlated with an increased level of advanced glycation end products (AGEs). In this study, we investigated the participation of reactive oxygen species (ROS) and the involvements of apoptosis signal-regulating kinase 1 (ASK1)/mitogen-activated protein kinase (MAPK) kinases (MKKs)/p38 MAPK and nuclear factor κB (NF-κB) pathways in AGE-induced apoptosis-mediated cardiac dysfunctions. The antioxidant and therapeutic effects of a novel ASK1 inhibitor, AGI-1067, were also studied. Myocardium and isolated primary myocytes were exposed to AGEs and treated with AGI-1067. Invasive hemodynamic and echocardiographic assessments were used to evaluate the cardiac functions. ROS formation was evaluated by dihydroethidium fluorescence staining. A terminal deoxynucleotidyl transferase dUTP nick end labelling assay was used to detect the apoptotic cells. ASK1 and NADPH activities were determined by kinase assays. The association between ASK1 and thioredoxin 1 (Trx1) was assessed by immunoprecipitation. Western blotting was used to evaluate the phosphorylation and expression levels of proteins. Our results showed that AGE exposure significantly activated ASK1/MKKs/p38 MAPK, which led to increased cardiac apoptosis and cardiac impairments. AGI-1067 administration inhibited the activation of MKKs/p38 MAPK by inhibiting the disassociation of ASK1 and Trx1, which suppressed the AGE-induced myocyte apoptosis. Moreover, the NF-κB activation as well as the ROS generation was inhibited. As a result, cardiac functions were improved. Our findings suggested that AGI-1067 recovered AGE-induced cardiac dysfunction by blocking both ASK1/MKKs/p38 and NF-κB apoptotic signaling pathways.
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Affiliation(s)
- Zhongwei Liu
- Key Laboratory of Biomedical Information Engineering of Ministry of Education School of Life Science and Technology Xi'an Jiaotong University China.,Department of Cardiology Shaanxi Provincial People's Hospital Xi'an China.,Department of Vascular Surgery Brigham and Women's Hospital Boston MA USA
| | - Shixiang Zheng
- Department of Vascular Surgery Brigham and Women's Hospital Boston MA USA.,Department of Critical Care Medicine Union Hospital of Fujian Medical University Fuzhou China
| | - Xi Wang
- Department of Vascular Surgery Brigham and Women's Hospital Boston MA USA.,Department of Obstetrics and Gynecology The Second Xiangya Hospital Central South University Changsha China
| | - Chuan Qiu
- Department of Biostatistics & Bioinformatics School of Public Health & Tropical Medicine Tulane University New Orleans LA USA
| | - Yan Guo
- Key Laboratory of Biomedical Information Engineering of Ministry of Education School of Life Science and Technology Xi'an Jiaotong University China
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Improvement of hyperglycemia in a murine model of insulin resistance and high glucose- and inflammasome-mediated IL-1β expressions in macrophages by silymarin. Chem Biol Interact 2018; 290:12-18. [DOI: 10.1016/j.cbi.2018.05.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2017] [Revised: 01/09/2018] [Accepted: 05/08/2018] [Indexed: 12/17/2022]
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33
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Cho YJ, Lee JE, Park MJ, O'Malley BW, Han SJ. Bufalin suppresses endometriosis progression by inducing pyroptosis and apoptosis. J Endocrinol 2018; 237:255-269. [PMID: 29636364 PMCID: PMC5943165 DOI: 10.1530/joe-17-0700] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Accepted: 04/10/2018] [Indexed: 12/14/2022]
Abstract
The steroid receptor coactivator (SRC)-1 isoform/estrogen receptor (ER)-β axis has an essential role in endometriosis progression. In this context, therefore, bufalin was employed as a 'tool compound' to evaluate inhibitors of SRC in alternative endometriosis treatment. Bufalin effectively suppressed the growth of primary human endometrial stroma cells isolated from endometriosis patients compared to women without endometriosis and immortalized human endometrial epithelial and stromal cells expressing the SRC-1 isoform compared to their parental cells in vitroIn vivo, compared to the vehicle, bufalin treatment significantly suppressed the growth of endometriotic lesions in mice with surgically induced endometriosis because bufalin disrupted the functional axis of SRC-1 isoform/ERβ by increasing SRC-1 isoform protein stability, hyperactivating the transcriptional activity of the SRC-1 isoform and degrading the ERβ protein by proteasome 26S subunit, non-ATPase 2 in endometriotic lesions. Bufalin treatment elevated the apoptosis signaling in epithelial cells of endometriotic lesions. In stromal cells of endometriotic lesions, bufalin treatment increased the levels of pyroptosis markers (caspase 1 and the active form of interleukin 1β) and reduced proliferation. In addition, bufalin treatment increased the expression levels of endoplasmic reticulum-stress (ERS) markers (PKR-like ER kinase, protein disulfide isomerase and binding immunoglobulin) in endometriotic lesions. Collectively, the bufalin-induced disruption of the SRC-1 isoform/ERβ axis might induce apoptosis, pyroptosis and ERS signaling in endometriotic lesions, causing the suppression of endometriosis. Therefore, future generations of SRC-modulators could be employed as an alternative medical approach for endometriosis treatment.
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Affiliation(s)
- Yeon Jean Cho
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
- Department of Obstetrics and Gynecology, Dong-A University, College of Medicine, Busan, Republic of Korea
| | - Jiyeun E Lee
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
| | - Mi Jin Park
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
| | - Bert W O'Malley
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
- Center for Reproductive Medicine, Baylor College of Medicine, Houston, Texas, USA
| | - Sang Jun Han
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
- Center for Reproductive Medicine, Baylor College of Medicine, Houston, Texas, USA
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Monoamine oxidase-dependent endoplasmic reticulum-mitochondria dysfunction and mast cell degranulation lead to adverse cardiac remodeling in diabetes. Cell Death Differ 2018; 25:1671-1685. [PMID: 29459772 PMCID: PMC6015497 DOI: 10.1038/s41418-018-0071-1] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Revised: 01/07/2018] [Accepted: 01/18/2018] [Indexed: 12/11/2022] Open
Abstract
Monoamine oxidase (MAO) inhibitors ameliorate contractile function in diabetic animals, but the mechanisms remain unknown. Equally elusive is the interplay between the cardiomyocyte alterations induced by hyperglycemia and the accompanying inflammation. Here we show that exposure of primary cardiomyocytes to high glucose and pro-inflammatory stimuli leads to MAO-dependent increase in reactive oxygen species that causes permeability transition pore opening and mitochondrial dysfunction. These events occur upstream of endoplasmic reticulum (ER) stress and are abolished by the MAO inhibitor pargyline, highlighting the role of these flavoenzymes in the ER/mitochondria cross-talk. In vivo, streptozotocin administration to mice induced oxidative changes and ER stress in the heart, events that were abolished by pargyline. Moreover, MAO inhibition prevented both mast cell degranulation and altered collagen deposition, thereby normalizing diastolic function. Taken together, these results elucidate the mechanisms underlying MAO-induced damage in diabetic cardiomyopathy and provide novel evidence for the role of MAOs in inflammation and inter-organelle communication. MAO inhibitors may be considered as a therapeutic option for diabetic complications as well as for other disorders in which mast cell degranulation is a dominant phenomenon.
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35
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Inflammation induced ER stress affects absorptive intestinal epithelial cells function and integrity. Int Immunopharmacol 2018; 55:336-344. [DOI: 10.1016/j.intimp.2017.12.016] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2017] [Revised: 12/11/2017] [Accepted: 12/12/2017] [Indexed: 02/07/2023]
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36
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Zhang X, Fu Y, Li H, Shen L, Chang Q, Pan L, Hong S, Yin X. H3 relaxin inhibits the collagen synthesis via ROS- and P2X7R-mediated NLRP3 inflammasome activation in cardiac fibroblasts under high glucose. J Cell Mol Med 2018; 22:1816-1825. [PMID: 29314607 PMCID: PMC5824385 DOI: 10.1111/jcmm.13464] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2017] [Accepted: 10/23/2017] [Indexed: 12/19/2022] Open
Abstract
Excessive production of reactive oxygen species (ROS) and P2X7R activation induced by high glucose increases NLRP3 inflammasome activation, which contributes to the pathogenesis of diabetic cardiomyopathy. Although H3 relaxin has been shown to inhibit cardiac fibrosis induced by isoproterenol, the mechanism has not been well studied. Here, we demonstrated that high glucose (HG) induced the collagen synthesis by activation of the NLRP3 inflammasome, leading to caspase‐1 activation, interleukin‐1β (IL‐1β) and IL‐18 secretion in neonatal rat cardiac fibroblasts. Moreover, we used a high‐glucose model with neonatal rat cardiac fibroblasts and showed that the activation of ROS and P2X7R was augmented and that ROS‐ and P2X7R‐mediated NLRP3 inflammasome activation was critical for the collagen synthesis. Inhibition of ROS and P2X7R decreased NLRP3 inflammasome‐mediated collagen synthesis, similar to the effects of H3 relaxin. Furthermore, H3 relaxin reduced the collagen synthesis via ROS‐ and P2X7R‐mediated NLRP3 inflammasome activation in response to HG. These results provide a mechanism by which H3 relaxin alleviates NLRP3 inflammasome‐mediated collagen synthesis through the inhibition of ROS and P2X7R under HG conditions and suggest that H3 relaxin represents a potential drug for alleviating cardiac fibrosis in diabetic cardiomyopathy.
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Affiliation(s)
- Xiaohui Zhang
- The Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yu Fu
- The Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Hui Li
- The Department of Cardiology, The Fifth hospital of Harbin, Harbin, China
| | - Li Shen
- The Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Qing Chang
- The Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Liya Pan
- The Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Siting Hong
- The Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xinhua Yin
- The Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
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Mechanisms of epithelial thickening due to IL-1 signalling blockade and TNF-α administration differ during wound repair and regeneration. Differentiation 2018; 99:10-20. [DOI: 10.1016/j.diff.2017.12.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2017] [Revised: 11/20/2017] [Accepted: 12/11/2017] [Indexed: 01/20/2023]
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38
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Yang Y, Liu L, Naik I, Braunstein Z, Zhong J, Ren B. Transcription Factor C/EBP Homologous Protein in Health and Diseases. Front Immunol 2017; 8:1612. [PMID: 29230213 PMCID: PMC5712004 DOI: 10.3389/fimmu.2017.01612] [Citation(s) in RCA: 146] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2017] [Accepted: 11/07/2017] [Indexed: 12/13/2022] Open
Abstract
C/EBP homologous protein (CHOP), known also as DNA damage-inducible transcript 3 and as growth arrest and DNA damage-inducible protein 153 (GADD153), is induced in response to certain stressors. CHOP is universally acknowledged as a main conduit to endoplasmic reticulum stress-induced apoptosis. Ongoing research established the existence of CHOP-mediated apoptosis signaling networks, for which novel downstream targets are still being determined. However, there are studies that contradict this notion and assert that apoptosis is not the only mechanism by which CHOP plays in the development of pathologies. In this review, insights into the roles of CHOP in pathophysiology are summarized at the molecular and cellular levels. We further focus on the newest advances that implicate CHOP in human diseases including cancer, diabetes, neurodegenerative disorders, and notably, fibrosis.
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Affiliation(s)
- Yuan Yang
- Center for Molecular Medicine, Medical School of Yangtze University, Jingzhou, China
- Department of Radiology, Medical School of Yangtze University, Jingzhou, China
| | - Lian Liu
- Department of Pharmacology, Medical School of Yangtze University, Jingzhou, China
| | - Ishan Naik
- Cardiovascular Research Institute, Case Western Reserve University, Cleveland, OH, United States
| | - Zachary Braunstein
- Boonshoft School of Medicine, Wright State University, Dayton, OH, United States
| | - Jixin Zhong
- Cardiovascular Research Institute, Case Western Reserve University, Cleveland, OH, United States
| | - Boxu Ren
- Center for Molecular Medicine, Medical School of Yangtze University, Jingzhou, China
- Department of Radiology, Medical School of Yangtze University, Jingzhou, China
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39
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Zhang Y, Cui L, Guan G, Wang J, Qiu C, Yang T, Guo Y, Liu Z. Matrine suppresses cardiac fibrosis by inhibiting the TGF‑β/Smad pathway in experimental diabetic cardiomyopathy. Mol Med Rep 2017; 17:1775-1781. [PMID: 29138820 PMCID: PMC5780122 DOI: 10.3892/mmr.2017.8054] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2017] [Accepted: 10/19/2017] [Indexed: 12/24/2022] Open
Abstract
Cardiac fibrosis is one of the pathological characteristics of diabetic cardiomyopathy (DbCM). Matrine treatment has proven to be effective in cases of organ fibrosis and cardiovascular diseases. In the present study, the anti-fibrosis-associated cardioprotective effects of matrine on DbCM were investigated. Rats with experimental DbCM were administered matrine orally. Cardiac functions were evaluated using invasive hemodynamic examinations. Cardiac compliance was assessed in isolated hearts. Using Sirius Red and fluorescence staining, the collagen in diabetic hearts was visualized. MTT assay was used to select non-cytotoxic concentrations of matrine, which were subsequently used to treat isolated cardiac fibroblasts incubated under various conditions. Western blotting was performed to assess activation of the transforming growth factor-β1 (TGF-β1)/Smad signaling pathway. Rats with DbCM exhibited impaired heart compliance and left ventricular (LV) functions. Excessive collagen deposition in cardiac tissue was also observed. Furthermore, TGF-β1/R-Smad (Smad2/3) signaling was revealed to be markedly activated; however, the expression of inhibitory Smad (I-Smad, also termed Smad7) was reduced in DbCM. Matrine administration led to a marked recovery in LV function and heart compliance by exerting inhibitory effects on TGF-β1/R-Smad signaling pathway-induced fibrosis without affecting I-Smad. Incubation with a high concentration of glucose triggered the TGF-β1/R-Smad (Smad2/3) signaling pathway and suppressed I-Smad signaling transduction in cultured cardiac fibroblasts, which led to an increase in the synthesis of collagen. After cardiac fibroblasts had been treated with matrine at non-cytotoxic concentrations without affecting I-Smad, matrine blocked TGF-β1/R-Smad signaling transduction to repress collagen production and deposition. In conclusion, the results of the present study demonstrated that TGF-β1/Smad signaling-associated cardiac fibrosis is involved in the impairment of heart compliance and LV dysfunction in DbCM. By exerting therapeutic effects against cardiac fibrosis via its influence on TGF-β1/Smad signaling, matrine exhibited cardioprotective effects in DbCM.
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Affiliation(s)
- Yong Zhang
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China
| | - Lei Cui
- Department of Ultrasonography, Xianyang Central Hospital, Xianyang, Shaanxi 712000, P.R. China
| | - Gongchang Guan
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China
| | - Junkui Wang
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China
| | - Chuan Qiu
- Department of Biostatistics and Bioinformatics, School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA 70112, USA
| | - Tielin Yang
- Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi 710000, P.R. China
| | - Yan Guo
- Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi 710000, P.R. China
| | - Zhongwei Liu
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China
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40
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Zhu H, Gao Y, Zhu S, Cui Q, Du J. Klotho Improves Cardiac Function by Suppressing Reactive Oxygen Species (ROS) Mediated Apoptosis by Modulating Mapks/Nrf2 Signaling in Doxorubicin-Induced Cardiotoxicity. Med Sci Monit 2017; 23:5283-5293. [PMID: 29107939 PMCID: PMC5687120 DOI: 10.12659/msm.907449] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Background Anthracyclines-induced cardiotoxicity has become one of the major restrictions of their clinical applications. Klotho showed cardioprotective effects. This study aimed to investigate the effects and possible mechanisms of klotho on doxorubicin (DOX)-induced cardiotoxicity. Material/Methods Rats and isolated myocytes were exposed to DOX and treated with exogenous klotho. Specific inhibitors and siRNAs silencing MAPKs were also used to treat the animals and/or myocytes. An invasive hemodynamic method was used to determine cardiac functions. Intracellular ROS generation was evaluated by DHE staining. Western blotting was used to determine the phosphorylation levels of JNK, ERK, and p38 MAPKs in plasma extracts and Nrf2 in nuclear extracts. Nuclear translocation of Nrf2 in myocytes was evaluated by immunohistochemistry. Cell apoptosis was evaluated by TUNEL assay and flow cytometry. Results Klotho treatment improved DOX-induced cardiac dysfunction in rats. The DOX-induced ROS accumulation and cardiac apoptosis were attenuated by klotho. Impaired phosphorylations of MAPKs, Nrf2 translocation and expression levels of HO1 and Prx1 were also attenuated by klotho treatment. However, the anti-oxidant and anti-apoptotic effects of klotho on DOX-exposed myocardium and myocytes were impaired by both specific inhibitors and siRNAs against MAPKs. Moreover, the recovery effects of klotho on phosphorylations of MAPKs, Nrf2 translocation and expression levels of HO1 and Prx1 were also impaired by specific inhibitors and siRNAs against MAPKs. Conclusions By recovering the activation of MAPKs signaling, klotho improved cardiac function loss which was triggered by DOX-induced ROS mediated cardiac apoptosis.
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Affiliation(s)
- Huolan Zhu
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi, China (mainland)
| | - Yan Gao
- ECG Exam Room, Function Testing Lab, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi, China (mainland)
| | - Shunming Zhu
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi, China (mainland)
| | - Qianwei Cui
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi, China (mainland)
| | - Jie Du
- Health Examination Center, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi, China (mainland)
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41
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Pan L, Hong Z, Yu L, Gao Y, Zhang R, Feng H, Su L, Wang G. Shear stress induces human aortic endothelial cell apoptosis via interleukin‑1 receptor‑associated kinase 2‑induced endoplasmic reticulum stress. Mol Med Rep 2017; 16:7205-7212. [PMID: 28944871 PMCID: PMC5865847 DOI: 10.3892/mmr.2017.7524] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Accepted: 05/12/2017] [Indexed: 02/05/2023] Open
Abstract
Atherosclerosis is characterized by localized lesions distributed in the arterial tree due to the shear stress produced by blood flow. Endothelial cells are directly affected by alterations in blood flow. Dysfunction and injury to endothelial cells has been hypothesized to initiate the pathological processes of atherosclerosis. The present study aimed to investigate the mechanism of shear stress‑induced endothelial cellular apoptosis. Shear stress was generated using an artificial device to mimic the impact of disturbed blood flow on cultured human aortic endothelial cells (HAECs). Cellular apoptosis was assessed using a terminal deoxynucleotidyl transferase dUTP nick end labeling assay; an ELISA assay was used to detect the produced interleukin (IL)‑1β; specific small interfering (si)RNA was used to knockdown the expression of interleukin‑1 receptor‑associated kinase 2 (IRAK2) in HAECs and the expression levels of 78 kDa glucose‑regulated protein, DNA damage‑inducible transcript 3 protein (CHOP), IRAK2 and IL‑1β were evaluated using western blotting. The results of the present study demonstrated that artificial shear stress induced endoplasmic reticulum (ER) stress, IL‑1β production and apoptosis in HAECs in a time‑dependent manner. The inhibition of ER stress, and treatment with interleukin‑1 receptor antagonist protein and siRNA against IRAK2 attenuated shear stress‑induced CHOP signaling‑mediated cellular apoptosis. Therefore, overproduction of IL‑1β exacerbated shear stress‑induced ER stress‑mediated apoptosis via the IRAK2/CHOP signaling pathway in endothelial cells.
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Affiliation(s)
- Longfei Pan
- Department of Emergency Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
| | - Zhou Hong
- Department of Emergency Medicine, The Fifth Hospital of Xi'an, Xi'an, Shaanxi 710082, P.R. China
| | - Lei Yu
- Department of Basic Medicine, Xi'an Medical College, Xi'an, Shaanxi 710068, P.R. China
| | - Yanxia Gao
- Department of Emergency Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
| | - Rui Zhang
- Department of Emergency Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
| | - Hui Feng
- Department of Emergency Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
| | - Lijuan Su
- Department of Emergency Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
| | - Gang Wang
- Department of Emergency Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
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Mirroring the CANTOS revolution: is anti-inflammatory therapy for diabetes just around the corner? Cardiovasc Diabetol 2017; 16:91. [PMID: 28724428 PMCID: PMC5517949 DOI: 10.1186/s12933-017-0573-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Accepted: 07/09/2017] [Indexed: 12/20/2022] Open
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The Effects of Diabetes Induction on the Rat Heart: Differences in Oxidative Stress, Inflammatory Cells, and Fibrosis between Subendocardial and Interstitial Myocardial Areas. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2017; 2017:5343972. [PMID: 28781721 PMCID: PMC5525092 DOI: 10.1155/2017/5343972] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Accepted: 05/08/2017] [Indexed: 12/26/2022]
Abstract
Diabetic cardiomyopathy (DCM) is characterized by cardiac remodeling and impaired diastolic function that may lead to heart failure. The aim of this study was to evaluate oxidative stress, inflammatory cells, and fibrosis in both subendocardial (SEN) and interstitial (INT) areas of the myocardium. Male Wistar rats were allocated to 2 groups of 9 animals, a control (CT) group and streptozotocin-induced diabetes (DM). After 8 weeks, echocardiography morphometry, protein expression, and confocal microscopy in SEN and INT areas of the left ventricle (LV) were performed. The echocardiographic analysis showed that diabetes induction leads to cardiac dilation, hypertrophy, and LV diastolic dysfunction. As compared to CT, the induction of diabetes increased inflammatory cells and fibrosis in both SEN and INT areas of DM myocardium and increased ROS generation only in SEN. Comparing the SEN and INT areas in the DM group, inflammatory cells and fibrosis in SEN were greater than in INT. In conclusion, diabetic myocardium SEN area, wherein oxidative stress was more pronounced, is more susceptible to cardiac dysfunction than INT area. This finding can be important for the understanding of the heart remodeling process occurring in DCM and perhaps to engender targeted therapies to attenuate or revert DCM-related diastolic dysfunction.
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Peiró C, Lorenzo Ó, Carraro R, Sánchez-Ferrer CF. IL-1β Inhibition in Cardiovascular Complications Associated to Diabetes Mellitus. Front Pharmacol 2017; 8:363. [PMID: 28659798 PMCID: PMC5468794 DOI: 10.3389/fphar.2017.00363] [Citation(s) in RCA: 103] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2017] [Accepted: 05/26/2017] [Indexed: 01/15/2023] Open
Abstract
Diabetes mellitus (DM) is a chronic disease that affects nowadays millions of people worldwide. In adults, type 2 diabetes mellitus (T2DM) accounts for the majority of all diagnosed cases of diabetes. The course of the T2DM is characterized by insulin resistance and a progressive loss of β-cell mass. DM is associated with a number of related complications, among which cardiovascular complications and atherosclerosis are the main cause of morbidity and mortality in patients suffering from the disease. DM is acknowledged as a low-grade chronic inflammatory state characterized by the over-secretion of pro-inflammatory cytokines, including interleukin (IL)-1β, which reinforce inflammatory signals thus contributing to the development of complications. In this context, the pharmacological approaches to treat diabetes should not only correct hyperglycaemia, but also attenuate inflammation and prevent the development of metabolic and cardiovascular complications. Over the last years, novel biological drugs have been developed to antagonize the pathophysiological actions of IL-1β. The drugs currently used in clinical practice are anakinra, a recombinant form of the naturally occurring IL-1 receptor antagonist, the soluble decoy receptor rilonacept and the monoclonal antibodies canakinumab and gevokizumab. This review will summarize the main experimental and clinical findings obtained with pharmacological IL-1β inhibitors in the context of the cardiovascular complications of DM, and discuss the perspectives of IL-1β inhibitors as novel therapeutic tools for treating these patients.
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Affiliation(s)
- Concepción Peiró
- Department of Pharmacology, School of Medicine, Universidad Autónoma de MadridMadrid, Spain.,Instituto de Investigación Sanitaria Hospital Universitario de La Paz (IdiPAZ)Madrid, Spain
| | - Óscar Lorenzo
- Department of Medicine, School of Medicine, Universidad Autónoma de MadridMadrid, Spain.,Instituto de Investigación Sanitaria Fundación Jiménez DíazMadrid, Spain
| | - Raffaele Carraro
- Department of Medicine, School of Medicine, Universidad Autónoma de MadridMadrid, Spain.,Service of Endocrinology, Hospital de La PrincesaMadrid, Spain.,Instituto de Investigación Sanitaria Hospital de La PrincesaMadrid, Spain
| | - Carlos F Sánchez-Ferrer
- Department of Pharmacology, School of Medicine, Universidad Autónoma de MadridMadrid, Spain.,Instituto de Investigación Sanitaria Hospital Universitario de La Paz (IdiPAZ)Madrid, Spain
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Younis A, Eskenazi D, Goldkorn R, Leor J, Naftali-Shani N, Fisman EZ, Tenenbaum A, Goldenberg I, Klempfner R. The addition of vildagliptin to metformin prevents the elevation of interleukin 1ß in patients with type 2 diabetes and coronary artery disease: a prospective, randomized, open-label study. Cardiovasc Diabetol 2017; 16:69. [PMID: 28532406 PMCID: PMC5440983 DOI: 10.1186/s12933-017-0551-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2017] [Accepted: 05/13/2017] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Patients with type 2 diabetes present with an accelerated atherosclerotic process. Animal evidence indicates that dipeptidyl peptidase-4 inhibitors (gliptins) have anti-inflammatory and anti-atherosclerotic effects, yet clinical data are scarcely available. DESIGN AND METHODS A prospective, randomized, open-label study was performed in 60 patients with coronary artery disease (CAD) and type 2 diabetes, who participated in a cardiac rehabilitation program. After a washout period of 3 weeks, patients were randomized in a 2:1 ratio to receive combined vildagliptin/metformin therapy (intervention group: n = 40) vs. metformin alone (control group: n = 20) for a total of 12 weeks. Blinded assessment of interleukin-1ß (IL-1ß, the primary endpoint), hemoglobin A1c (HbA1c), and high sensitivity C reactive protein (hsCRP), were performed at baseline and after 12 weeks. RESULTS Mean age of study patients was 67 ± 9 years, 75% were males, and baseline HbA1c and inflammatory markers levels were similar between the two groups. At 12 weeks of follow up, levels of IL-1ß, hsCRP, and HbA1c were significantly lower in the intervention group as compared with the control group. There was a continuous elevation of IL-1ß among the control group, which was not observed in the intervention group (49 vs. 4%, respectively; p < 0.001). The hsCRP was lowered by 60% in the vildagliptin/metformin group vs. 23% in the metformin group (p < 0.01). Moreover, a significant relative reduction of the HbA1c was seen in the intervention group (7% reduction, p < 0.03). CONCLUSION The addition of vildagliptin to metformin treatment in patients with type 2 diabetes and CAD led to a significant suppression of the IL-1ß elevation during follow up. A significant relative reduction of hsCRP and HbA1c in the intervention group was also observed. Trial registration NCT01604213.
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Affiliation(s)
- Arwa Younis
- The Leviev Heart Center, Sheba Medical Center, Tel Hashomer, Sheba Road 2, 52620 Ramat Gan, Israel
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Dana Eskenazi
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Ronen Goldkorn
- The Leviev Heart Center, Sheba Medical Center, Tel Hashomer, Sheba Road 2, 52620 Ramat Gan, Israel
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Jonathan Leor
- The Leviev Heart Center, Sheba Medical Center, Tel Hashomer, Sheba Road 2, 52620 Ramat Gan, Israel
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Nili Naftali-Shani
- The Leviev Heart Center, Sheba Medical Center, Tel Hashomer, Sheba Road 2, 52620 Ramat Gan, Israel
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Enrique Z. Fisman
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
- Cardiovascular Diabetology Research Foundation, Holon, Israel
| | - Alexander Tenenbaum
- The Leviev Heart Center, Sheba Medical Center, Tel Hashomer, Sheba Road 2, 52620 Ramat Gan, Israel
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
- Cardiovascular Diabetology Research Foundation, Holon, Israel
| | - Ilan Goldenberg
- The Leviev Heart Center, Sheba Medical Center, Tel Hashomer, Sheba Road 2, 52620 Ramat Gan, Israel
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
- Heart Research Follow-up Program, University of Rochester, Rochester, NY USA
| | - Robert Klempfner
- The Leviev Heart Center, Sheba Medical Center, Tel Hashomer, Sheba Road 2, 52620 Ramat Gan, Israel
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
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Liu Z, Zhang Y, Tang Z, Xu J, Ma M, Pan S, Qiu C, Guan G, Wang J. Matrine attenuates cardiac fibrosis by affecting ATF6 signaling pathway in diabetic cardiomyopathy. Eur J Pharmacol 2017; 804:21-30. [PMID: 28373137 DOI: 10.1016/j.ejphar.2017.03.061] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2017] [Revised: 03/27/2017] [Accepted: 03/30/2017] [Indexed: 01/01/2023]
Abstract
Cardiac function and compliance impairments are the features of cardiac fibrosis. Matrine shows therapeutic effects on cardiovascular diseases and organ fibrosis. In this study, we examined the therapeutic effects and mechanisms of matrine on cardiac fibrosis of DbCM. Matrine was administrated orally to rats with DbCM. Cardiac functions and compliance were evaluated. The collagen deposition was visualized by sirius red staining. Real-time PCR was used to determine the expression level of miRNA. Western blotting was performed to assess the protein expression. NFAT nuclear translocation was evaluated by fluorescent immunochemistry staining and Western blotting. Intracellular calcium level was assessed by fura-2/AM staining. A colorimetric method was used to determine calcineurin enzymatic activity. Impaired cardiac function and compliance were observed in rats with DbCM. Increased collagen deposition in cardiac tissue was found. Furthermore, ATF6 signaling was activated, leading to intracellular calcium accumulation and NFAT activation which further initiated ECM gene expressions. Matrine administration recovered cardiac function and improved compliance by exerting inhibitory effects against ATF6 signaling- induced fibrosis. The high- glucose incubation induced ATF6 signaling activation in cultured CFs to increase the synthesis of ECM. Matrine blocked the ATF6 signaling in CFs to inhibit ECM synthesis within non- cytotoxic concentrations. ATF6 signaling induced cardiac fibrosis was one of the mechanisms involved in DbCM, which was characterized by loss of cardiac compliance and functions. Matrine attenuated cardiac compliance and improved left ventricular functions by exerting therapeutic effects against cardiac fibrosis via affecting ATF6 signaling pathway.
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Affiliation(s)
- Zhongwei Liu
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an 710000, China; Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710000, China.
| | - Yong Zhang
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an 710000, China.
| | - Zhiguo Tang
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an 710000, China.
| | - Jing Xu
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an 710000, China.
| | - Meijuan Ma
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an 710000, China.
| | - Shuo Pan
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an 710000, China.
| | - Chuan Qiu
- Department of Biostatistics & Bioinformatics, School of Public Health & Tropical Medicine, Tulane University, New Orleans 70112, USA.
| | - Gongchang Guan
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an 710000, China.
| | - Junkui Wang
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an 710000, China.
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Frati G, Schirone L, Chimenti I, Yee D, Biondi-Zoccai G, Volpe M, Sciarretta S. An overview of the inflammatory signalling mechanisms in the myocardium underlying the development of diabetic cardiomyopathy. Cardiovasc Res 2017; 113:378-388. [PMID: 28395009 DOI: 10.1093/cvr/cvx011] [Citation(s) in RCA: 176] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2016] [Accepted: 01/20/2017] [Indexed: 02/05/2023] Open
Abstract
Heart failure is a highly morbid and mortal clinical condition that represents the last stage of most cardiovascular disorders. Diabetes is strongly associated with an increased incidence of heart failure and directly promotes cardiac hypertrophy, fibrosis, and apoptosis. These changes, in turn, contribute to the development of ventricular dysfunction. The clinical condition associated with the spectrum of cardiac abnormalities induced by diabetes is termed diabetic cardiomyopathy. Myocardial inflammation has recently emerged as a pathophysiological process contributing to cardiac hypertrophy, fibrosis, and dysfunction in cardiac diseases. Myocardial inflammation is also implicated in the development of diabetic cardiomyopathy. Several molecular mechanisms link diabetes to myocardial inflammation. The NF-κB signalling pathway and the renin-angiotensin-aldosterone system are strongly activated in the diabetic heart, thereby promoting myocardial inflammation. Advanced glycation end-products and damage-associated molecular pattern molecules also represent strong triggers for inflammation. The mediators resulting from this inflammatory process modulate specific intracellular signalling mechanisms in cardiac cells that promote the development of diabetic cardiomyopathy. This review article will provide an overview of the signalling molecular mechanisms linking diabetic cardiomyopathy to myocardial inflammation.
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Affiliation(s)
- Giacomo Frati
- Department of Medical and Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, 04100 Latina (LT), Italy
- Department of AngioCardioNeurology, IRCCS Neuromed, 86077 Pozzilli (IS), Italy
| | - Leonardo Schirone
- Department of Medical and Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, 04100 Latina (LT), Italy
| | - Isotta Chimenti
- Department of Medical and Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, 04100 Latina (LT), Italy
| | - Derek Yee
- Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Giuseppe Biondi-Zoccai
- Department of Medical and Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, 04100 Latina (LT), Italy
- Department of AngioCardioNeurology, IRCCS Neuromed, 86077 Pozzilli (IS), Italy
| | - Massimo Volpe
- Department of Medical and Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, 04100 Latina (LT), Italy
- Department of AngioCardioNeurology, IRCCS Neuromed, 86077 Pozzilli (IS), Italy
| | - Sebastiano Sciarretta
- Department of Medical and Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, 04100 Latina (LT), Italy
- Department of AngioCardioNeurology, IRCCS Neuromed, 86077 Pozzilli (IS), Italy
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Shen NY, Bi JB, Zhang JY, Zhang SM, Gu JX, Qu K, Liu C. Hydrogen-rich water protects against inflammatory bowel disease in mice by inhibiting endoplasmic reticulum stress and promoting heme oxygenase-1 expression. World J Gastroenterol 2017; 23:1375-1386. [PMID: 28293084 PMCID: PMC5330822 DOI: 10.3748/wjg.v23.i8.1375] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2016] [Revised: 12/20/2016] [Accepted: 01/17/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the therapeutic effect of hydrogen-rich water (HRW) on inflammatory bowel disease (IBD) and to explore the potential mechanisms involved.
METHODS Male mice were randomly divided into the following four groups: control group, in which the mice received equivalent volumes of normal saline (NS) intraperitoneally (ip); dextran sulfate sodium (DSS) group, in which the mice received NS ip (5 mL/kg body weight, twice per day at 8 am and 5 pm) for 7 consecutive days after IBD modeling; DSS + HRW group, in which the mice received HRW (in the same volume as the NS treatment) for 7 consecutive days after IBD modeling; and DSS + HRW + ZnPP group, in which the mice received HRW (in the same volume as the NS treatment) and ZnPP [a heme oxygenase-1 (HO-1) inhibitor, 25 mg/kg] for 7 consecutive days after IBD modeling. IBD was induced by feeding DSS to the mice, and blood and colon tissues were collected on the 7th d after IBD modeling to determine clinical symptoms, colonic inflammation and the potential mechanisms involved.
RESULTS The DSS + HRW group exhibited significantly attenuated weight loss and a lower extent of disease activity index compared with the DSS group on the 7th d (P < 0.05). HRW exerted protective effects against colon shortening and colonic wall thickening in contrast to the DSS group (P < 0.05). The histological study demonstrated milder inflammation in the DSS + HRW group, which was similar to normal inflammatory levels, and the macroscopic and microcosmic damage scores were lower in this group than in the DSS group (P < 0.05). The oxidative stress parameters, including MDA and MPO in the colon, were significantly decreased in the DSS + HRW group compared with the DSS group (P < 0.05). Simultaneously, the protective indicators, superoxide dismutase and glutathione, were markedly increased with the use of HRW. Inflammatory factors were assessed, and the results showed that the DSS + HRW group exhibited significantly reduced levels of TNF-α, IL-6 and IL-1β compared with the DSS group (P < 0.05). In addition, the pivotal proteins involved in endoplasmic reticulum (ER) stress, including p-eIF2α, ATF4, XBP1s and CHOP, were dramatically reduced after HRW treatment in contrast to the control group (P < 0.05). Furthermore, HRW treatment markedly up-regulated HO-1 expression, and the use of ZnPP obviously reversed the protective role of HRW. In the DSS + HRW + ZnPP group, colon shortening and colonic wall thickening were significantly aggravated, and the macroscopic damage scores were similar to those of the DSS + HRW group (P < 0.05). The histological study also showed more serious colonic damage that was similar to the DSS group.
CONCLUSION HRW has a significant therapeutic potential in IBD by inhibiting inflammatory factors, oxidative stress and ER stress and by up-regulating HO-1 expression.
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Tiny molecule, big power: Multi-target approach for curcumin in diabetic cardiomyopathy. Nutrition 2017; 34:47-54. [DOI: 10.1016/j.nut.2016.09.005] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Revised: 08/28/2016] [Accepted: 09/20/2016] [Indexed: 02/07/2023]
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50
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Tang JY, Jin P, He Q, Lu LH, Ma JP, Gao WL, Bai HP, Yang J. Naringenin ameliorates hypoxia/reoxygenation-induced endoplasmic reticulum stress-mediated apoptosis in H9c2 myocardial cells: involvement in ATF6, IRE1α and PERK signaling activation. Mol Cell Biochem 2016; 424:111-122. [PMID: 27785700 DOI: 10.1007/s11010-016-2848-1] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2016] [Accepted: 10/14/2016] [Indexed: 02/07/2023]
Abstract
Naringenin, a flavanone mainly derived from grapes and citrus fruits, has been reported to exhibit cardioprotective effects. Accumulating evidence has confirmed that endoplasmic reticulum (ER) stress-mediated apoptosis participates in the process of myocardial ischemia/reperfusion injury and inhibiting ER stress is a potential therapeutic target/strategy in preventing cardiovascular diseases. Herein, the current study was designed to investigate whether naringenin protects H9c2 myocardial cells against hypoxia/reoxygenation (H/R) injury via attenuating ER stress or ER stress-mediated apoptosis. Our results showed that naringenin treatment resulted in obvious increases in the viability of H9c2 cells and the expression of Bcl-2 (anti-apoptotic protein), and decreases in the morphological changes of apoptotic cells, the activity of caspase-3 and the expression of Bax (pro-apoptotic protein) in H/R-treated H9c2 cells, implying the protective effects of naringenin against H/R-induced injury. In addition, naringenin also significantly reversed H/R-induced ER stress as evidenced by the up-regulation of Glucose-regulated protein 78, C/EBP homologous protein and Cleaved caspase-12 proteins. Meanwhile, naringenin remarkably reversed H/R-induced the increases in the expression of cleaved activating transcription factor 6 (ATF6) and phosphorylation levels of phospho-extracellular regulated protein kinases (PERK) and inositol-requiring enzyme-1α (IRE1α) in H9c2 cells. Finally, we found that ATF6 siRNA, PERK siRNA or IRE1α siRNA abolished H/R-induced cytotoxicity and apoptosis in H9c2 cells. In conclusion, these results confirmed that ER stress-mediated apoptosis contributes to the protection effects of naringenin against H/R injury, which is potentially involved in ATF6, IRE1α and PERK signaling activation.
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Affiliation(s)
- Jia-You Tang
- Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, 169 W Changle West Road, Xi'an, 710032, Shanxi, People's Republic of China
| | - Ping Jin
- Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, 169 W Changle West Road, Xi'an, 710032, Shanxi, People's Republic of China
| | - Qing He
- Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, 169 W Changle West Road, Xi'an, 710032, Shanxi, People's Republic of China
| | - Lin-He Lu
- Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, 169 W Changle West Road, Xi'an, 710032, Shanxi, People's Republic of China
| | - Ji-Peng Ma
- Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, 169 W Changle West Road, Xi'an, 710032, Shanxi, People's Republic of China
| | - Wei-Lun Gao
- Department of Cardiovascular Surgery, General Hospital of Ningxia Medical University, Yinchuan, 750004, Ningxia, People's Republic of China
| | - He-Ping Bai
- Department of Thoracic and Cardiovascular Surgery, The Second Hospital of Yulin, Yulin, 719000, Shanxi, People's Republic of China
| | - Jian Yang
- Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, 169 W Changle West Road, Xi'an, 710032, Shanxi, People's Republic of China.
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