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Frontiers in Endocrinology 2022Diabetic cardiomyopathy (DCM) is a pathophysiological condition induced by diabetes mellitus that often causes heart failure (HF). However, their mechanistic...
Diabetic cardiomyopathy (DCM) is a pathophysiological condition induced by diabetes mellitus that often causes heart failure (HF). However, their mechanistic relationships remain unclear. This study aimed to identify immune gene signatures and molecular mechanisms of DCM. Microarray data from the Gene Expression Omnibus (GEO) database from patients with DCM were subjected to weighted gene co-expression network analysis (WGCNA) identify co-expression modules. Core expression modules were intersected with the immune gene database. We analyzed and mapped protein-protein interaction (PPI) networks using the STRING database and MCODE and filtering out 17 hub genes using cytoHubba software. Finally, potential transcriptional regulatory factors and therapeutic drugs were identified and molecular docking between gene targets and small molecules was performed. We identified five potential immune biomarkers: proteosome subunit beta type-8 (), nuclear factor kappa B1 (), albumin (), endothelin 1 (), and estrogen receptor 1 (). Their expression levels in animal models were consistent with the changes observed in the datasets. showed significant differences in expression in both the dataset and the validation model by real-time quantitative PCR (qPCR) and Western blotting(WB). Subsequently, we confirmed that the potential transcription factors upstream of were PRDM5 and KLF4, as its expression was positively correlated with the expression of the two transcription factors. To repurpose known therapeutic drugs, a connectivity map (CMap) database was retrieved, and nine candidate compounds were identified. Finally, molecular docking simulations of the proteins encoded by the five genes with small-molecule drugs were performed. Our data suggest that may play a key role in the development of DCM and is a potential DCM biomarker.
Topics: Animals; Biomarkers; Computational Biology; Diabetes Mellitus; Diabetic Cardiomyopathies; Gene Expression Profiling; Gene Regulatory Networks; Molecular Docking Simulation; Transcription Factors
PubMed: 36046789
DOI: 10.3389/fendo.2022.933635 -
Redox Biology Jun 2023Brain natriuretic peptide (BNP) belongs to the family of natriuretic peptides, which are responsible for a wide range of actions. Diabetic cardiomyopathy (DCM) is often...
Brain natriuretic peptide (BNP) belongs to the family of natriuretic peptides, which are responsible for a wide range of actions. Diabetic cardiomyopathy (DCM) is often associated with increased BNP levels. This present research intends to explore the role of BNP in the development of DCM and the underlying mechanisms. Diabetes was induced in mice using streptozotocin (STZ). Primary neonatal cardiomyocytes were treated with high glucose. It was found that the levels of plasma BNP started to increase at 8 weeks after diabetes, which preceded the development of DCM. Addition of exogenous BNP promoted Opa1-mediated mitochondrial fusion, inhibited mitochondrial oxidative stress, preserved mitochondrial respiratory capacity and prevented the development of DCM, while knockdown of endogenous BNP exacerbated mitochondrial dysfunction and accelerated DCM. Opa1 knockdown attenuated the aforementioned protective action of BNP both in vivo and in vitro. BNP-induced mitochondrial fusion requires the activation of STAT3, which facilitated Opa1 transcription by binding to its promoter regions. PKG, a crucial signaling biomolecule in the BNP signaling pathway, interacted with STAT3 and induced its activation. Knockdown of NPRA (the receptor of BNP) or PKG blunted the promoting effect of BNP on STAT3 phosphorylation and Opa1-mediated mitochondrial fusion. The results of this study demonstrate for the first time that there is a rise in BNP during the early stages of DCM as a compensatory protection mechanism. BNP is a novel mitochondrial fusion activator in protecting against hyperglycemia-induced mitochondrial oxidative injury and DCM through the activation of NPRA-PKG-STAT3-Opa1 signaling pathway.
Topics: Animals; Mice; Diabetes Mellitus; Diabetic Cardiomyopathies; Mitochondrial Dynamics; Myocytes, Cardiac; Natriuretic Peptide, Brain; Signal Transduction; Cyclic GMP-Dependent Protein Kinases
PubMed: 37116257
DOI: 10.1016/j.redox.2023.102702 -
Basic Research in Cardiology Nov 2020Type 2 diabetic cardiomyopathy features Ca signaling abnormalities, notably an altered mitochondrial Ca handling. We here aimed to study if it might be due to a...
Type 2 diabetic cardiomyopathy features Ca signaling abnormalities, notably an altered mitochondrial Ca handling. We here aimed to study if it might be due to a dysregulation of either the whole Ca homeostasis, the reticulum-mitochondrial Ca coupling, and/or the mitochondrial Ca entry through the uniporter. Following a 16-week high-fat high-sucrose diet (HFHSD), mice developed cardiac insulin resistance, fibrosis, hypertrophy, lipid accumulation, and diastolic dysfunction when compared to standard diet. Ultrastructural and proteomic analyses of cardiac reticulum-mitochondria interface revealed tighter interactions not compatible with Ca transport in HFHSD cardiomyocytes. Intramyocardial adenoviral injections of Ca sensors were performed to measure Ca fluxes in freshly isolated adult cardiomyocytes and to analyze the direct effects of in vivo type 2 diabetes on cardiomyocyte function. HFHSD resulted in a decreased IP3R-VDAC interaction and a reduced IP3-stimulated Ca transfer to mitochondria, with no changes in reticular Ca level, cytosolic Ca transients, and mitochondrial Ca uniporter function. Disruption of organelle Ca exchange was associated with decreased mitochondrial bioenergetics and reduced cell contraction, which was rescued by an adenovirus-mediated expression of a reticulum-mitochondria linker. An 8-week diet reversal was able to restore cardiac insulin signaling, Ca transfer, and cardiac function in HFHSD mice. Therefore, our study demonstrates that the reticulum-mitochondria Ca miscoupling may play an early and reversible role in the development of diabetic cardiomyopathy by disrupting primarily the mitochondrial bioenergetics. A diet reversal, by counteracting the MAM-induced mitochondrial Ca dysfunction, might contribute to restore normal cardiac function and prevent the exacerbation of diabetic cardiomyopathy.
Topics: Animals; Calcium; Calcium Channels; Calcium Signaling; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Diet, High-Fat; Dietary Sucrose; Endoplasmic Reticulum; Energy Metabolism; Excitation Contraction Coupling; Inositol 1,4,5-Trisphosphate; Inositol 1,4,5-Trisphosphate Receptors; Insulin Resistance; Male; Mice, Inbred C57BL; Mitochondria, Heart; Mitochondrial Proteins; Myocytes, Cardiac; Voltage-Dependent Anion Channel 1
PubMed: 33258101
DOI: 10.1007/s00395-020-00835-7 -
Metabolism: Clinical and Experimental Sep 2023The prevalence of type 2 diabetes mellitus (T2DM) has increased over the past decades. Diabetic cardiomyopathy (DCM) is the leading cause of death in T2DM patients,...
BACKGROUND
The prevalence of type 2 diabetes mellitus (T2DM) has increased over the past decades. Diabetic cardiomyopathy (DCM) is the leading cause of death in T2DM patients, however, the mechanism underlying DCM remains largely unknown. Here, we aimed to investigate the role of cardiac PR-domain containing 16 (PRDM16) in T2DM.
METHODS
We modeled mice with cardiac-specific deletion of Prdm16 by crossing the floxed Prdm16 mouse model with the cardiomyocyte-specific Cre transgenic mouse. The mice were continuously fed a chow diet or high-fat diet combining with streptozotocin (STZ) for 24 weeks to establish a T2DM model. DB/DB and adequate control mice were given a single intravenous injection of adeno-associated virus 9 (AAV9) carrying cardiac troponin T (cTnT) promoter-driven small hairpin RNA targeting PRDM16 (AAV9-cTnT-shPRDM16) from the retro-orbital venous plexus to knockout Prdm16 in the myocardium. There were at least 12 mice in each group. Mitochondrial morphology and function were detected using transmission electron microscopy, western blot determining the protein level of mitochondrial respiratory chain complex, mitotracker staining and Seahorse XF Cell Mito Stress Test Kit. Untargeted metabolomics analysis and RNA-seq analysis were performed to determine the molecular and metabolic changes associated with Prdm16 deficiency. BODIPY and TUNEL staining were used to detect lipid uptake and apoptosis. Co-immunoprecipitation and ChIP assays were conducted to examine the potential underlying mechanism.
RESULTS
Prdm16 cardiac-specific deficiency accelerated cardiomyopathy and worsened cardiac dysfunction in mice with T2DM, aggravating mitochondrial dysfunction and apoptosis both in vivo and in vitro, while PRDM16 overexpression the deterioration. Prdm16 deficiency also caused cardiac lipid accumulation resulting in metabolic and molecular alterations in T2DM mouse models. Co-IP and luciferase assays confirmed that PRDM16 targeted and regulated the transcriptional activity, expression and interaction of PPAR-α and PGC-1α, while the overexpression of PPAR-α and PGC-1α reversed Prdm16 deficiency-induced cellular dysfunction in T2DM model. Moreover, PRDM16 regulated PPAR-α and PGC-1α and affected mitochondrial function by mainly depending on epigenetic regulation of H3K4me3.
CONCLUSIONS
These findings suggest that PRDM16 exerted its protective role in myocardial lipid metabolism and mitochondrial function in T2DM in a histone lysine methyltransferase activity-dependent manner by regulating PPAR-α and PGC-1α.
Topics: Animals; Mice; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Epigenesis, Genetic; Lipids; Myocytes, Cardiac; Peroxisome Proliferator-Activated Receptors; Transcription Factors
PubMed: 37433344
DOI: 10.1016/j.metabol.2023.155658 -
Clinica Chimica Acta; International... Jun 2021Diabetic cardiomyopathy is an important irreversible chronic cardiovascular complication in diabetic patients. This condition is described as early diastolic... (Review)
Review
Diabetic cardiomyopathy is an important irreversible chronic cardiovascular complication in diabetic patients. This condition is described as early diastolic dysfunction, myocardial fibrosis, cardiac hypertrophy, systolic dysfunction and other complex pathophysiological events, which ultimately lead to heart failure. Despite these characteristics, the underlying mechanisms resulting in diabetic cardiomyopathy are still unknown. With the developments in molecular biotechnology, increasing evidence shows that circRNAs play critical roles in the pathogenesis of diabetic cardiomyopathy. The purpose of this review is to summarize recent studies on the role of circRNAs in the pathophysiological process to provide novel prevention and treatment strategies for diabetic cardiomyopathy, oxidative stress, inflammation, endothelial dysfunction, myocardial fibrosis and cell death in diabetic cardiomyopathy.
Topics: Diabetes Mellitus; Diabetic Cardiomyopathies; Fibrosis; Heart Diseases; Humans; Oxidative Stress; RNA, Circular
PubMed: 33711326
DOI: 10.1016/j.cca.2021.03.001 -
Cardiovascular Diabetology Jul 2022Diabetes is a metabolic disorder that affects millions of people worldwide. Diabetic heart disease (DHD) comprises coronary artery disease, heart failure, cardiac... (Review)
Review
Diabetes is a metabolic disorder that affects millions of people worldwide. Diabetic heart disease (DHD) comprises coronary artery disease, heart failure, cardiac autonomic neuropathy, peripheral arterial disease, and diabetic cardiomyopathy. The onset and progression of DHD have been attributed to molecular alterations in response to hyperglycemia in diabetes. In this context, microRNAs (miRNAs) have been demonstrated to have a significant role in the development and progression of DHD. In addition to their effects on the host cells, miRNAs can be released into circulation after encapsulation within the exosomes. Exosomes are extracellular nanovesicles ranging from 30 to 180 nm in diameter secreted by all cell types. They carry diverse cargos that are altered in response to various conditions in their parent cells. Exosomal miRNAs have been extensively studied in recent years due to their role and therapeutic potential in DHD. This review will first provide an overview of exosomes, their biogenesis and function, followed by the role of exosomes in cardiovascular disease and then focuses on the known role of exosomes and associated miRNAs in DHD.
Topics: Cardiovascular Diseases; Diabetes Mellitus; Diabetic Cardiomyopathies; Exosomes; Humans; MicroRNAs
PubMed: 35778763
DOI: 10.1186/s12933-022-01544-2 -
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 -
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 -
Sheng Li Xue Bao : [Acta Physiologica... Jun 2022Histone methylation is one of the key post-translational modifications that plays a critical role in various heart diseases, including diabetic cardiomyopathy. A great... (Review)
Review
Histone methylation is one of the key post-translational modifications that plays a critical role in various heart diseases, including diabetic cardiomyopathy. A great deal of evidence has shown that histone methylation is closely related to hyperglycemia, insulin resistance, lipid and advanced glycation end products deposition, inflammatory and oxidative stress, endoplasmic reticulum stress and cell apoptosis, and these pathological factors play an important role in the pathogenesis of diabetic cardiomyopathy. In order to provide a novel theoretical basis and potential targets for the treatment of diabetic cardiomyopathy from the perspective of epigenetics, this review discussed and elucidated the association between histone methylation and the pathogenesis of diabetic cardiomyopathy in details.
Topics: Diabetes Mellitus; Diabetic Cardiomyopathies; Histones; Humans; Methylation; Oxidative Stress; Protein Processing, Post-Translational
PubMed: 35770643
DOI: No ID Found -
Frontiers of Medicine Feb 2022Cardiovascular diseases account for approximately 80% of deaths among individuals with diabetes mellitus, with diabetic cardiomyopathy as the major diabetic... (Review)
Review
Cardiovascular diseases account for approximately 80% of deaths among individuals with diabetes mellitus, with diabetic cardiomyopathy as the major diabetic cardiovascular complication. Hyperglycemia is a symptom that abnormally activates multiple downstream pathways and contributes to cardiac hypertrophy, fibrosis, apoptosis, and other pathophysiological changes. Although glycemic control has long been at the center of diabetes therapy, multicenter randomized clinical studies have revealed that intensive glycemic control fails to reduce heart failure-associated hospitalization and mortality in patients with diabetes. This finding indicates that hyperglycemic stress persists in the cardiovascular system of patients with diabetes even if blood glucose level is tightly controlled to the normal level. This process is now referred to as hyperglycemic memory (HGM) phenomenon. We briefly reviewed herein the current advances that have been achieved in research on the underlying mechanisms of HGM in diabetic cardiomyopathy.
Topics: Cardiovascular Diseases; Diabetes Complications; Diabetes Mellitus; Diabetic Cardiomyopathies; Humans; Hyperglycemia; Multicenter Studies as Topic
PubMed: 34921674
DOI: 10.1007/s11684-021-0881-2