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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 -
Hypertension Research : Official... Mar 2018Chronic diabetic complications are classified as microvascular or macrovascular and contribute to mortality and loss of quality of life. Hyperglycemia plays a critical... (Review)
Review
Chronic diabetic complications are classified as microvascular or macrovascular and contribute to mortality and loss of quality of life. Hyperglycemia plays a critical role in the pathogenesis of microvascular complications, such as diabetic retinopathy, incipient nephropathy, and neuropathy, while atherosclerosis contributes to the pathogenesis of macrovascular complications. Diabetes mellitus and hypertension are frequently present together. Among many microvascular diabetic complications, hypertension plays a predominant role in the progression of diabetic nephropathy by glomerular hyperfiltration. Hypertension also induces atherosclerosis in diabetes. Thus, hypertension is a high-risk factor for both microvascular and macrovascular chronic diabetic complications. In this review, we summarize the current knowledge on the pathophysiological mechanisms of microvascular and macrovascular chronic diabetic complications with particular emphasis on the contribution of hypertension. We also briefly discuss various options available for the treatment of each diabetic complication.
Topics: Blood Vessels; Capillaries; Diabetes Complications; Diabetic Angiopathies; Diabetic Cardiomyopathies; Humans; Hypertension
PubMed: 29353881
DOI: 10.1038/s41440-017-0008-y -
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 -
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 -
Heart (British Cardiac Society) Feb 2019
Topics: Biomarkers; Cardiac Imaging Techniques; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Heart Failure; Humans; Metabolism; Preventive Health Services; Prognosis; Ventricular Remodeling
PubMed: 30337334
DOI: 10.1136/heartjnl-2016-310342 -
Cardiovascular Diabetology Feb 2017Diabetic cardiomyopathy (DCM) is a cardiac dysfunction which affects approximately 12% of diabetic patients, leading to overt heart failure and death. However, there is... (Review)
Review
Diabetic cardiomyopathy (DCM) is a cardiac dysfunction which affects approximately 12% of diabetic patients, leading to overt heart failure and death. However, there is not an efficient and specific methodology for DCM diagnosis, possibly because molecular mechanisms are not fully elucidated, and it remains asymptomatic for many years. Also, DCM frequently coexists with other comorbidities such as hypertension, obesity, dyslipidemia, and vasculopathies. Thus, human DCM is not specifically identified after heart failure is established. In this sense, echocardiography has been traditionally considered the gold standard imaging test to evaluate the presence of cardiac dysfunction, although other techniques may cover earlier DCM detection by quantification of altered myocardial metabolism and strain. In this sense, Phase-Magnetic Resonance Imaging and 2D/3D-Speckle Tracking Echocardiography may potentially diagnose and stratify diabetic patients. Additionally, this information could be completed with a quantification of specific plasma biomarkers related to related to initial stages of the disease. Cardiotrophin-1, activin A, insulin-like growth factor binding protein-7 (IGFBP-7) and Heart fatty-acid binding protein have demonstrated a stable positive correlation with cardiac hypertrophy, contractibility and steatosis responses. Thus, we suggest a combination of minimally-invasive diagnosis tools for human DCM recognition based on imaging techniques and measurements of related plasma biomarkers.
Topics: Diabetic Cardiomyopathies; Echocardiography; Humans; Magnetic Resonance Imaging; Positron-Emission Tomography; Tomography, Emission-Computed, Single-Photon
PubMed: 28231848
DOI: 10.1186/s12933-017-0506-x -
The Korean Journal of Internal Medicine May 2017The global burden of diabetes mellitus and its related complications are currently increasing. Diabetes mellitus affects the heart through various mechanisms including... (Review)
Review
The global burden of diabetes mellitus and its related complications are currently increasing. Diabetes mellitus affects the heart through various mechanisms including microvascular impairment, metabolic disturbance, subcellular component abnormalities, cardiac autonomic dysfunction, and a maladaptive immune response. Eventually, diabetes mellitus can cause functional and structural changes in the myocardium without coronary artery disease, a disorder known as diabetic cardiomyopathy (DCM). There are many diagnostic tools and management options for DCM, although it is difficult to detect its development and effectively prevent its progression. In this review, we summarize the current research regarding the pathophysiology and pathogenesis of DCM. Moreover, we discuss emerging diagnostic evaluation methods and treatment strategies for DCM, which may help our understanding of its underlying mechanisms and facilitate the identification of possible new therapeutic targets.
Topics: Cardiac Imaging Techniques; Diabetic Cardiomyopathies; Heart; Humans
PubMed: 28415836
DOI: 10.3904/kjim.2016.208 -
Journal of Cardiovascular Pharmacology Dec 2017Diabetic cardiomyopathy is a heart disease in diabetic patients, identified as ventricular dysfunction in the absence of coronary artery disease and hypertension. The... (Review)
Review
Diabetic cardiomyopathy is a heart disease in diabetic patients, identified as ventricular dysfunction in the absence of coronary artery disease and hypertension. The molecular mechanisms underlying diabetic cardiomyopathy are still poorly understood. The protein and lipid kinase phosphoinositide 3-kinases (PI3Ks) have been suggested to regulate cardiac injury during diabetes. In this review, we will summarize the role of different PI3K isoforms and of their downstream signaling in the pathogenesis of diabetic cardiomyopathy, including the regulation of cardiac metabolism, contractility, hypertrophy, myocardial cell death, and inflammation.
Topics: Animals; Diabetic Cardiomyopathies; Humans; Myocytes, Cardiac; Phosphatidylinositol 3-Kinases
PubMed: 28654509
DOI: 10.1097/FJC.0000000000000511 -
Comprehensive Physiology Mar 2017Diabetic cardiomyopathy (DCM) was first recognized more than four decades ago and occurred independent of cardiovascular diseases or hypertension in both type 1 and type... (Review)
Review
Diabetic cardiomyopathy (DCM) was first recognized more than four decades ago and occurred independent of cardiovascular diseases or hypertension in both type 1 and type 2 diabetic patients. The exact mechanisms underlying this disease remain incompletely understood. Several pathophysiological bases responsible for DCM have been proposed, including the presence of hyperglycemia, nonenzymatic glycosylation of large molecules (e.g., proteins), energy metabolic disturbance, mitochondrial damage and dysfunction, impaired calcium handling, reactive oxygen species formation, inflammation, cardiac cell death, and cardiac hypertrophy and fibrosis, leading to impairment of cardiac contractile functions. Increasing evidence also indicates the phenomenon called "metabolic memory" for diabetes-induced cardiovascular complications, for which epigenetic modulation seemed to play an important role, suggesting that the aforementioned pathogenic bases may be regulated by epigenetic modification. Therefore, this review aims at briefly summarizing the current understanding of the pathophysiological bases for DCM. Although how epigenetic mechanisms play a role remains incompletely understood now, extensive clinical and experimental studies have implicated its importance in regulating the cardiac responses to diabetes, which are believed to shed insight into understanding of the pathophysiological and epigenetic mechanisms for the development of DCM and its possible prevention and/or therapy. © 2017 American Physiological Society. Compr Physiol 7:693-711, 2017.
Topics: Animals; Apoptosis; Cardiomegaly; DNA Methylation; Diabetic Cardiomyopathies; Epigenesis, Genetic; Extracellular Matrix; Fibrosis; Humans; MicroRNAs; Myocardium; Ventricular Dysfunction, Left
PubMed: 28333387
DOI: 10.1002/cphy.c160021 -
Acta Diabetologica Aug 2021Growing interest has been accumulated in the definition of worsening effects of diabetes in the cardiovascular system. This is associated with epidemiological data... (Review)
Review
Growing interest has been accumulated in the definition of worsening effects of diabetes in the cardiovascular system. This is associated with epidemiological data regarding the high incidence of heart failure (HF) in diabetic patients. To investigate the detrimental effects both of hyperglycemia and insulin resistance, a lot of preclinical models were developed. However, the evidence of pathogenic and histological alterations of the so-called diabetic cardiomyopathy (DCM) is still poorly understood in humans. Here, we provide a stringent literature analysis to investigate unique data regarding human DCM. This approach established that lipotoxic-related events might play a central role in the initiation and progression of human DCM. The major limitation in the acquisition of human data is due to the fact of heart specimen availability. Postmortem analysis revealed the end stage of the disease; thus, we need to gain knowledge on the pathogenic events from the early stages until cardiac fibrosis underlying the end-stage HF.
Topics: Diabetes Mellitus; Diabetic Cardiomyopathies; Disease Progression; Heart; Heart Failure; Humans; Hyperglycemia; Insulin Resistance; Myocardium
PubMed: 33791873
DOI: 10.1007/s00592-021-01705-x