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Clinical Epigenetics Apr 2024Diabetic cardiomyopathy (DCM) is a critical complication that poses a significant threat to the health of patients with diabetes. The intricate pathological mechanisms... (Review)
Review
Diabetic cardiomyopathy (DCM) is a critical complication that poses a significant threat to the health of patients with diabetes. The intricate pathological mechanisms of DCM cause diastolic dysfunction, followed by impaired systolic function in the late stages. Accumulating researches have revealed the association between DCM and various epigenetic regulatory mechanisms, including DNA methylation, histone modifications, non-coding RNAs, and other epigenetic molecules. Recently, a profound understanding of epigenetics in the pathophysiology of DCM has been broadened owing to advanced high-throughput technologies, which assist in developing potential therapeutic strategies. In this review, we briefly introduce the epigenetics regulation and update the relevant progress in DCM. We propose the role of epigenetic factors and non-coding RNAs (ncRNAs) as potential biomarkers and drugs in DCM diagnosis and treatment, providing a new perspective and understanding of epigenomics in DCM.
Topics: Humans; Diabetic Cardiomyopathies; DNA Methylation; Epigenomics; Epigenesis, Genetic; Histone Code; Diabetes Mellitus
PubMed: 38581056
DOI: 10.1186/s13148-024-01667-1 -
European Journal of Pharmacology Dec 2023Diabetes and its complications are increasing worldwide in the working population as well as in elders. Prolonged hyperglycemia results in damage to blood vessels of... (Review)
Review
Diabetes and its complications are increasing worldwide in the working population as well as in elders. Prolonged hyperglycemia results in damage to blood vessels of various tissues followed by organ damage. Hyperglycemia-induced damage in small blood vessels as in nephrons, retina, and neurons results in diabetic microvascular complications which involve nephropathy, retinopathy, and diabetic neuropathy. Additionally, damage in large blood vessels is considered as a macrovascular complication including diabetic cardiomyopathy. These long-term complications can result in organ failure and thus becomes the leading cause of diabetic-related mortality in patients. Members of the Forkhead Box O family (FOXO) are involved in various body functions including cell proliferation, metabolic processes, differentiation, autophagy, and apoptosis. Moreover, increasing shreds of evidence suggest the involvement of FOXO family members FOXO1, FOXO3, FOXO4, and FOXO6 in several chronic diseases including diabetes and diabetic complications. Hence, this review focuses on the role of FOXO transcription factors in the regulation of diabetic complications.
Topics: Humans; Aged; Forkhead Transcription Factors; Diabetes Complications; Diabetic Cardiomyopathies; Cell Differentiation; Hyperglycemia; Diabetes Mellitus
PubMed: 37838103
DOI: 10.1016/j.ejphar.2023.176089 -
Nature Metabolism Jun 2024Diabetic cardiomyopathy is characterized by myocardial lipid accumulation and cardiac dysfunction. Bile acid metabolism is known to play a crucial role in cardiovascular...
Diabetic cardiomyopathy is characterized by myocardial lipid accumulation and cardiac dysfunction. Bile acid metabolism is known to play a crucial role in cardiovascular and metabolic diseases. Takeda G-protein-coupled receptor 5 (TGR5), a major bile acid receptor, has been implicated in metabolic regulation and myocardial protection. However, the precise involvement of the bile acid-TGR5 pathway in maintaining cardiometabolic homeostasis remains unclear. Here we show decreased plasma bile acid levels in both male and female participants with diabetic myocardial injury. Additionally, we observe increased myocardial lipid accumulation and cardiac dysfunction in cardiomyocyte-specific TGR5-deleted mice (both male and female) subjected to a high-fat diet and streptozotocin treatment or bred on the diabetic db/db genetic background. Further investigation reveals that TGR5 deletion enhances cardiac fatty acid uptake, resulting in lipid accumulation. Mechanistically, TGR5 deletion promotes localization of CD36 on the plasma membrane through the upregulation of CD36 palmitoylation mediated by the palmitoyl acyltransferase DHHC4. Our findings indicate that the TGR5-DHHC4 pathway regulates cardiac fatty acid uptake, which highlights the therapeutic potential of targeting TGR5 in the management of diabetic cardiomyopathy.
Topics: Animals; Receptors, G-Protein-Coupled; Diabetic Cardiomyopathies; Mice; Male; Female; Fatty Acids; Humans; Mice, Knockout; Bile Acids and Salts; Diet, High-Fat; CD36 Antigens; Myocardium; Lipid Metabolism; Myocytes, Cardiac; Diabetes Mellitus, Experimental
PubMed: 38698281
DOI: 10.1038/s42255-024-01036-5 -
Redox Biology Feb 2024Ketone bodies are considered as an alternative energy source for diabetic cardiomyopathy (DCM) and can improve the energy supply of the heart muscle, suggesting that it...
Ketone bodies are considered as an alternative energy source for diabetic cardiomyopathy (DCM) and can improve the energy supply of the heart muscle, suggesting that it may be an important area of research and development as a therapeutic target for DCM. Cumulative cardiovascular trials have shown that sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce cardiovascular events in diabetic populations. Whether SGLT2 inhibitors improve DCM by enhancing ketone body metabolism remains and whether they help prevent oxidative damage remains to be clarified. Here, we present the combined results of nine GSE datasets for diabetic cardiomyopathy (GSE215979, GSE161931, GSE145294, GSE161052, GSE173384, GSE123975, GSE161827, GSE210612, and GSE5606). We found significant up-regulated gene 3-hydroxymethylglutaryl CoA synthetase 2 (HMGCS2) and down-regulated gene 3-hydroxybutyrate dehydrogenase (BDH1) and 3-oxoacid CoA-transferase1 (OXCT1), respectively. Based on the analysis of the constructed protein interaction network, it was found that HMGCS2 was in the core position of the interaction network. In addition, Gene ontology (GO) enrichment analysis mainly focused on redox process, acyl-CoA metabolic process, catalytic activity, redox enzyme activity and mitochondria. The activity of HMGCS2 in DCM heart was increased, while the expression of ketolysis enzymes BDH1 and OXCT1 was inhibited. In vivo, Empagliflozin (Emp) treated DCM group significantly decreased ventricular weight, myocardial cell cross-sectional area, and myocardial fibrosis. In addition, Emp further promoted the activity of BDH1 and OXCT1, increased the utilization of ketone bodies, further promoted the activity of HMGCS2 in DCM, and increased the synthesis of ketone bodies, prevented mitochondrial breakage and dysfunction, increased myocardial ATP to provide sufficient energy, inhibited oxidative stress and apoptosis of cardiac cells ex vivo, and improved the myocardial dysfunction of DCM. Emp can improve mitochondrial dysfunction in diabetic cardiomyopathy by regulating ketone body metabolism and oxidative stress. These findings provide a theoretical basis for evaluating Emp as a treatment for DCM.
Topics: Humans; Diabetic Cardiomyopathies; Oxidative Stress; Myocytes, Cardiac; Ketone Bodies; Mitochondrial Diseases; Diabetes Mellitus; Benzhydryl Compounds; Glucosides
PubMed: 38160540
DOI: 10.1016/j.redox.2023.103010 -
Biomedicine & Pharmacotherapy =... Dec 2023Diabetic cardiomyopathy is a chronic cardiovascular complication caused by diabetes that is characterized by changes in myocardial structure and function, ultimately... (Review)
Review
Diabetic cardiomyopathy is a chronic cardiovascular complication caused by diabetes that is characterized by changes in myocardial structure and function, ultimately leading to heart failure and even death. Mitochondria serve as the provider of energy to cardiomyocytes, and mitochondrial dysfunction plays a central role in the development of diabetic cardiomyopathy. In response to a series of pathological changes caused by mitochondrial dysfunction, the mitochondrial quality control system is activated. The mitochondrial quality control system (including mitochondrial biogenesis, fusion and fission, and mitophagy) is core to maintaining the normal structure of mitochondria and performing their normal physiological functions. However, mitochondrial quality control is abnormal in diabetic cardiomyopathy, resulting in insufficient mitochondrial fusion and excessive fission within the cardiomyocyte, and fragmented mitochondria are not phagocytosed in a timely manner, accumulating within the cardiomyocyte resulting in cardiomyocyte injury. Currently, there is no specific therapy or prevention for diabetic cardiomyopathy, and glycemic control remains the mainstay. In this review, we first elucidate the pathogenesis of diabetic cardiomyopathy and explore the link between pathological mitochondrial quality control and the development of diabetic cardiomyopathy. Then, we summarize how clinically used hypoglycemic agents (including sodium-glucose cotransport protein 2 inhibitions, glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, thiazolidinediones, metformin, and α-glucosidase inhibitors) exert cardioprotective effects to treat and prevent diabetic cardiomyopathy by targeting the mitochondrial quality control system. In addition, the mechanisms of complementary alternative therapies, such as active ingredients of traditional Chinese medicine, exercise, and lifestyle, targeting mitochondrial quality control for the treatment of diabetic cardiomyopathy are also added, which lays the foundation for the excavation of new diabetic cardioprotective drugs.
Topics: Humans; Diabetic Cardiomyopathies; Hypoglycemic Agents; Mitochondria; Myocardium; Myocytes, Cardiac; Diabetes Mellitus
PubMed: 37820568
DOI: 10.1016/j.biopha.2023.115669 -
JCI Insight Sep 2023Diabetic cardiomyopathy, an increasingly global epidemic and a major cause of heart failure with preserved ejection fraction (HFpEF), is associated with hyperglycemia,...
Diabetic cardiomyopathy, an increasingly global epidemic and a major cause of heart failure with preserved ejection fraction (HFpEF), is associated with hyperglycemia, insulin resistance, and intracardiomyocyte calcium mishandling. Here we identify that, in db/db mice with type 2 diabetes-induced HFpEF, abnormal remodeling of cardiomyocyte transverse-tubule microdomains occurs with downregulation of the membrane scaffolding protein cardiac bridging integrator 1 (cBIN1). Transduction of cBIN1 by AAV9 gene therapy can restore transverse-tubule microdomains to normalize intracellular distribution of calcium-handling proteins and, surprisingly, glucose transporter 4 (GLUT4). Cardiac proteomics revealed that AAV9-cBIN1 normalized components of calcium handling and GLUT4 translocation machineries. Functional studies further identified that AAV9-cBIN1 normalized insulin-dependent glucose uptake in diabetic cardiomyocytes. Phenotypically, AAV9-cBIN1 rescued cardiac lusitropy, improved exercise intolerance, and ameliorated hyperglycemia in diabetic mice. Restoration of transverse-tubule microdomains can improve cardiac function in the setting of diabetic cardiomyopathy and can also improve systemic glycemic control.
Topics: Animals; Mice; Blood Glucose; Diabetic Cardiomyopathies; Heart Failure; Calcium; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Stroke Volume; Anti-Arrhythmia Agents; Cardiotonic Agents; Myocytes, Cardiac; Hyperglycemia; Adaptor Proteins, Signal Transducing; Amino Acids; Enzyme Inhibitors; Genetic Therapy
PubMed: 37639557
DOI: 10.1172/jci.insight.166713 -
Circulation Research Mar 2024Chronic overconsumption of lipids followed by their excessive accumulation in the heart leads to cardiomyopathy. The cause of lipid-induced cardiomyopathy involves a...
BACKGROUND
Chronic overconsumption of lipids followed by their excessive accumulation in the heart leads to cardiomyopathy. The cause of lipid-induced cardiomyopathy involves a pivotal role for the proton-pump vacuolar-type H-ATPase (v-ATPase), which acidifies endosomes, and for lipid-transporter CD36, which is stored in acidified endosomes. During lipid overexposure, an increased influx of lipids into cardiomyocytes is sensed by v-ATPase, which then disassembles, causing endosomal de-acidification and expulsion of stored CD36 from the endosomes toward the sarcolemma. Once at the sarcolemma, CD36 not only increases lipid uptake but also interacts with inflammatory receptor TLR4 (Toll-like receptor 4), together resulting in lipid-induced insulin resistance, inflammation, fibrosis, and cardiac dysfunction. Strategies inducing v-ATPase reassembly, that is, to achieve CD36 reinternalization, may correct these maladaptive alterations. For this, we used NAD (nicotinamide adenine dinucleotide)-precursor nicotinamide mononucleotide (NMN), inducing v-ATPase reassembly by stimulating glycolytic enzymes to bind to v-ATPase.
METHODS
Rats/mice on cardiomyopathy-inducing high-fat diets were supplemented with NMN and for comparison with a cocktail of lysine/leucine/arginine (mTORC1 [mechanistic target of rapamycin complex 1]-mediated v-ATPase reassembly). We used the following methods: RNA sequencing, mRNA/protein expression analysis, immunofluorescence microscopy, (co)immunoprecipitation/proximity ligation assay (v-ATPase assembly), myocellular uptake of [H]chloroquine (endosomal pH), and [C]palmitate, targeted lipidomics, and echocardiography. To confirm the involvement of v-ATPase in the beneficial effects of both supplementations, mTORC1/v-ATPase inhibitors (rapamycin/bafilomycin A1) were administered. Additionally, 2 heart-specific v-ATPase-knockout mouse models (subunits VG1/Vd2) were subjected to these measurements. Mechanisms were confirmed in pharmacologically/genetically manipulated cardiomyocyte models of lipid overload.
RESULTS
NMN successfully preserved endosomal acidification during myocardial lipid overload by maintaining v-ATPase activity and subsequently prevented CD36-mediated lipid accumulation, CD36-TLR4 interaction toward inflammation, fibrosis, cardiac dysfunction, and whole-body insulin resistance. Lipidomics revealed C18:1-enriched diacylglycerols as lipid class prominently increased by high-fat diet and subsequently reversed/preserved by lysine/leucine/arginine/NMN treatment. Studies with mTORC1/v-ATPase inhibitors and heart-specific v-ATPase-knockout mice further confirmed the pivotal roles of v-ATPase in these beneficial actions.
CONCLUSION
NMN preserves heart function during lipid overload by preventing v-ATPase disassembly.
Topics: Animals; Mice; Rats; Adenosine Triphosphatases; Arginine; Cardiomyopathies; CD36 Antigens; Fibrosis; Inflammation; Insulin Resistance; Leucine; Lipids; Lysine; Mechanistic Target of Rapamycin Complex 1; Myocytes, Cardiac; Nicotinamide Mononucleotide; Toll-Like Receptor 4
PubMed: 38422177
DOI: 10.1161/CIRCRESAHA.123.322910 -
Frontiers in Cell and Developmental... 2023Cardiovascular diseases (CVDs) are one of the primary causes of mortality worldwide. An optimal mitochondrial function is central to supplying tissues with high energy... (Review)
Review
Cardiovascular diseases (CVDs) are one of the primary causes of mortality worldwide. An optimal mitochondrial function is central to supplying tissues with high energy demand, such as the cardiovascular system. In addition to producing ATP as a power source, mitochondria are also heavily involved in adaptation to environmental stress and fine-tuning tissue functions. Mitochondrial quality control (MQC) through fission, fusion, mitophagy, and biogenesis ensures the clearance of dysfunctional mitochondria and preserves mitochondrial homeostasis in cardiovascular tissues. Furthermore, mitochondria generate reactive oxygen species (ROS), which trigger the production of pro-inflammatory cytokines and regulate cell survival. Mitochondrial dysfunction has been implicated in multiple CVDs, including ischemia-reperfusion (I/R), atherosclerosis, heart failure, cardiac hypertrophy, hypertension, diabetic and genetic cardiomyopathies, and Kawasaki Disease (KD). Thus, MQC is pivotal in promoting cardiovascular health. Here, we outline the mechanisms of MQC and discuss the current literature on mitochondrial adaptation in CVDs.
PubMed: 38020895
DOI: 10.3389/fcell.2023.1290046 -
Ageing Research Reviews Feb 2024Diabetes mellitus (DM) is a chronic metabolic disease characterized by hyperglycaemia that seriously affects human health. Diabetic cardiomyopathy (DCM) is a major... (Review)
Review
Diabetes mellitus (DM) is a chronic metabolic disease characterized by hyperglycaemia that seriously affects human health. Diabetic cardiomyopathy (DCM) is a major cardiovascular complication and one of the main causes of death in patients with DM. Although DCM attracts great attention, and new therapeutic methods are continuously developed, there is a lack of effective treatment strategies. Therefore, exploring and targeting new signalling pathways related to the evolution of DCM becomes a hotspot and difficulty in the prevention and treatment of DCM. Pyroptosis is a newly discovered regulated cell death that is heavily dependent on the formation of plasma membrane pores by members of the gasdermin protein family and is reported to be involved in the occurrence, development, and pathogenesis of DCM. In this review, we focus on the molecular mechanisms of pyroptosis, its involvement in the relevant signalling pathways of DCM, and potential pyroptosis-targeting therapeutic strategies for the treatment of DCM. Our review provides new insights into the use of pyroptosis as a useful tool for the prevention and treatment of DCM and clarifies future research directions.
Topics: Humans; Diabetic Cardiomyopathies; Pyroptosis; Hyperglycemia; Inflammasomes; Diabetes Mellitus
PubMed: 38182080
DOI: 10.1016/j.arr.2023.102182 -
International Journal of Molecular... Oct 2023This study investigated modifications to the ubiquitin proteasome system (UPS) in a mouse model of type 2 diabetes mellitus (T2DM) and their relationship to heart...
This study investigated modifications to the ubiquitin proteasome system (UPS) in a mouse model of type 2 diabetes mellitus (T2DM) and their relationship to heart complications. mice heart tissues were compared with mice tissues using RNA sequencing, qRT-PCR, and protein analysis to identify cardiac UPS modifications associated with diabetes. The findings unveiled a distinctive gene profile in the hearts of mice with decreased levels of mRNA and increased levels of , indicating potential cardiac dysfunction. The mRNA levels of (deubiquitinating enzyme), , and (proteasome β-subunits) were down-regulated in mice, while the mRNA levels of RNF167 (E3 ligase) were increased. Corresponding LMP2 and LMP7 proteins were down-regulated in mice, and RNF167 was elevated in diabetic mice. The reduced expression of LMP2 and LMP7, along with increased RNF167 expression, may contribute to the future cardiac deterioration commonly observed in diabetes. This study enhances our understanding of UPS imbalances in the hearts of diabetic mice and raises questions about the interplay between the UPS and other cellular processes, such as autophagy. Further exploration in this area could provide valuable insights into the mechanisms underlying diabetic heart complications and potential therapeutic targets.
Topics: Mice; Animals; Proteasome Endopeptidase Complex; Ubiquitin; Diabetes Mellitus, Type 2; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Diabetes Complications; RNA, Messenger
PubMed: 37895057
DOI: 10.3390/ijms242015376