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Chinese Medical Journal Apr 2024Diabetic cardiomyopathy is defined as abnormal structure and function of the heart in the setting of diabetes, which could eventually develop heart failure and leads to... (Review)
Review
Diabetic cardiomyopathy is defined as abnormal structure and function of the heart in the setting of diabetes, which could eventually develop heart failure and leads to the death of the patients. Although blood glucose control and medications to heart failure show beneficial effects on this disease, there is currently no specific treatment for diabetic cardiomyopathy. Over the past few decades, the pathophysiology of diabetic cardiomyopathy has been extensively studied, and an increasing number of studies pinpoint that impaired mitochondrial energy metabolism is a key mediator as well as a therapeutic target. In this review, we summarize the latest research in the field of diabetic cardiomyopathy, focusing on mitochondrial damage and adaptation, altered energy substrates, and potential therapeutic targets. A better understanding of the mitochondrial energy metabolism in diabetic cardiomyopathy may help to gain more mechanistic insights and generate more precise mitochondria-oriented therapies to treat this disease.
Topics: Humans; Diabetic Cardiomyopathies; Energy Metabolism; Mitochondria; Animals
PubMed: 38527931
DOI: 10.1097/CM9.0000000000003075 -
Frontiers in Cardiovascular Medicine 2024Cardiomyopathy, a heterogeneous pathological condition characterized by changes in cardiac structure or function, represents a significant risk factor for the prevalence... (Review)
Review
Cardiomyopathy, a heterogeneous pathological condition characterized by changes in cardiac structure or function, represents a significant risk factor for the prevalence and mortality of cardiovascular disease (CVD). Research conducted over the years has led to the modification of definition and classification of cardiomyopathy. Herein, we reviewed seven of the most common types of cardiomyopathies, including Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC), diabetic cardiomyopathy, Dilated Cardiomyopathy (DCM), desmin-associated cardiomyopathy, Hypertrophic Cardiomyopathy (HCM), Ischemic Cardiomyopathy (ICM), and obesity cardiomyopathy, focusing on their definitions, epidemiology, and influencing factors. Cardiomyopathies manifest in various ways ranging from microscopic alterations in cardiomyocytes, to tissue hypoperfusion, cardiac failure, and arrhythmias caused by electrical conduction abnormalities. As pleiotropic Transcription Factors (TFs), the Krüppel-Like Factors (KLFs), a family of zinc finger proteins, are involved in regulating the setting and development of cardiomyopathies, and play critical roles in associated biological processes, including Oxidative Stress (OS), inflammatory reactions, myocardial hypertrophy and fibrosis, and cellular autophagy and apoptosis, particularly in diabetic cardiomyopathy. However, research into KLFs in cardiomyopathy is still in its early stages, and the pathophysiologic mechanisms of some KLF members in various types of cardiomyopathies remain unclear. This article reviews the roles and recent research advances in KLFs, specifically those targeting and regulating several cardiomyopathy-associated processes.
PubMed: 38516000
DOI: 10.3389/fcvm.2024.1342173 -
Annals of Clinical and Laboratory... Jan 2024Diabetic cardiomyopathy (DCM) is the most common cardiovascular complication of type 2 diabetes mellitus (T2DM). Patients affected with DCM face a notably higher risk of...
OBJECTIVE
Diabetic cardiomyopathy (DCM) is the most common cardiovascular complication of type 2 diabetes mellitus (T2DM). Patients affected with DCM face a notably higher risk of progressing to congestive heart failure compared to other populations. Myocardial hypertrophy, a clearly confirmed pathological change in DCM, plays an important role in the development of DCM, with abnormal Ca homeostasis serving as the key signal to induce myocardial hypertrophy. Therefore, investigating the mechanism of Ca transport is of great significance for the prevention and treatment of myocardial hypertrophy in T2DM.
METHODS
The rats included in the experiment were divided into wild type (WT) group and T2DM group. The T2DM rat model was established by feeding the rats with high-fat and high-sugar diets for three months combined with low dose of streptozotocin (100mg/kg). Afterwards, primary rat cardiomyocytes were isolated and cultured, and cardiomyocyte hypertrophy was induced through high-glucose treatment. Subsequently, mechanistic investigations were carried out through transfection with si-STIM1 and oe-STIM1. Western blot (WB) was used to detect the expression of the STIM1, Orai1 and p-CaMKII. qRT-PCR was used to detect mRNA levels of myocardial hypertrophy marker proteins. Cell surface area was detected using TRITC-Phalloidin staining, and intracellular Ca concentration in cardiomyocytes was measured using Fluo-4 fluorescence staining.
RESULTS
Through animal experiments, an upregulation of Orai1 and STIM1 was revealed in the rat model of myocardial hypertrophy induced by T2DM. Meanwhile, through cell experiments, it was found that in high glucose (HG)-induced hypertrophic cardiomyocytes, the expression of STIM1, Orai1, and p-CaMKII was upregulated, along with increased levels of store-operated Ca entry (SOCE) and abnormal Ca homeostasis. However, when STIM1 was downregulated in HG-induced cardiomyocytes, SOCE levels decreased and p-CaMKII was downregulated, resulting in an improvement in myocardial hypertrophy. To further elucidate the mechanism of action involving SOCE and CaMKII in T2DM-induced myocardial hypertrophy, high-glucose cardiomyocytes were respectively treated with BTP2 (SOCE blocker) and KN-93 (CaMKII inhibitor), and the results showed that STIM1 can mediate SOCE, thereby affecting the phosphorylation level of CaMKII and improving cardiomyocyte hypertrophy.
CONCLUSION
STIM1/Orai1-mediated SOCE regulates p-CaMKII levels, thereby inducing myocardial hypertrophy in T2DM.
Topics: Animals; Rats; Calcium; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cardiomegaly; Diabetes Mellitus, Type 2; Glucose; ORAI1 Protein; Stromal Interaction Molecule 1; Up-Regulation; Diabetic Cardiomyopathies; Rats, Sprague-Dawley; Male
PubMed: 38514055
DOI: No ID Found -
Theranostics 2024Adipose tissue (AT) dysfunction that occurs in both obesity and lipodystrophy is associated with the development of cardiomyopathy. However, it is unclear how...
Myocardin reverses insulin resistance and ameliorates cardiomyopathy by increasing IRS-1 expression in a murine model of lipodystrophy caused by adipose deficiency of vacuolar H-ATPase V0d1 subunit.
Adipose tissue (AT) dysfunction that occurs in both obesity and lipodystrophy is associated with the development of cardiomyopathy. However, it is unclear how dysfunctional AT induces cardiomyopathy due to limited animal models available. We have identified vacuolar H-ATPase subunit Vd1, encoded by , as a master regulator of adipogenesis, and adipose-specific deletion of () in mice caused generalized lipodystrophy and spontaneous cardiomyopathy. Using this unique animal model, we explore the mechanism(s) underlying lipodystrophy-related cardiomyopathy. mice developed cardiac hypertrophy at 12 weeks, and progressed to heart failure at 28 weeks. The mouse hearts exhibited excessive lipid accumulation and altered lipid and glucose metabolism, which are typical for obesity- and diabetes-related cardiomyopathy. The mice developed cardiac insulin resistance evidenced by decreased IRS-1/2 expression in hearts. Meanwhile, the expression of forkhead box O1 (FoxO1), a transcription factor which plays critical roles in regulating cardiac lipid and glucose metabolism, was increased. RNA-seq data and molecular biological assays demonstrated reduced expression of myocardin, a transcription coactivator, in mouse hearts. RNA interference (RNAi), luciferase reporter and ChIP-qPCR assays revealed the critical role of myocardin in regulating IRS-1 transcription through the CArG-like element in IRS-1 promoter. Reducing IRS-1 expression with RNAi increased FoxO1 expression, while increasing IRS-1 expression reversed myocardin downregulation-induced FoxO1 upregulation in cardiomyocytes. , restoring myocardin expression specifically in cardiomyocytes increased IRS-1, but decreased FoxO1 expression. As a result, the abnormal expressions of metabolic genes in hearts were reversed, and cardiac dysfunctions were ameliorated. Myocardin expression was also reduced in high fat diet-induced diabetic cardiomyopathy and palmitic acid-treated cardiomyocytes. Moreover, increasing systemic insulin resistance with rosiglitazone restored cardiac myocardin expression and improved cardiac functions in mice. mice are a novel animal model for studying lipodystrophy- or metabolic dysfunction-related cardiomyopathy. Moreover, myocardin serves as a key regulator of cardiac insulin sensitivity and metabolic homeostasis, highlighting myocardin as a potential therapeutic target for treating lipodystrophy- and diabetes-related cardiomyopathy.
Topics: Animals; Mice; Diabetic Cardiomyopathies; Disease Models, Animal; Glucose; Heart Failure; Insulin Resistance; Lipids; Lipodystrophy; Nuclear Proteins; Obesity; Trans-Activators; Vacuolar Proton-Translocating ATPases; Insulin Receptor Substrate Proteins
PubMed: 38505620
DOI: 10.7150/thno.93192 -
Journal of Cellular and Molecular... Apr 2024The increasing attention towards diabetic cardiomyopathy as a distinctive complication of diabetes mellitus has highlighted the need for standardized diagnostic criteria... (Review)
Review
The increasing attention towards diabetic cardiomyopathy as a distinctive complication of diabetes mellitus has highlighted the need for standardized diagnostic criteria and targeted treatment approaches in clinical practice. Ongoing research is gradually unravelling the pathogenesis of diabetic cardiomyopathy, with a particular emphasis on investigating various post-translational modifications. These modifications dynamically regulate protein function in response to changes in the internal and external environment, and their disturbance of homeostasis holds significant relevance for the development of chronic ailments. This review provides a comprehensive overview of the common post-translational modifications involved in the initiation and progression of diabetic cardiomyopathy, including O-GlcNAcylation, phosphorylation, methylation, acetylation and ubiquitination. Additionally, the review discusses drug development strategies for targeting key post-translational modification targets, such as agonists, inhibitors and PROTAC (proteolysis targeting chimaera) technology that targets E3 ubiquitin ligases.
Topics: Humans; Diabetic Cardiomyopathies; Protein Processing, Post-Translational; Ubiquitination; Phosphorylation; Ubiquitin-Protein Ligases; Diabetes Mellitus
PubMed: 38494853
DOI: 10.1111/jcmm.18158 -
International Immunopharmacology Apr 2024Diabetes is a global health problem whose common complication is diabetic cardiomyopathy, characterized by chronic inflammation of the heart muscle. Macrophages are the...
BACKGROUND
Diabetes is a global health problem whose common complication is diabetic cardiomyopathy, characterized by chronic inflammation of the heart muscle. Macrophages are the main white blood cells found in the resting heart. Therefore, we investigated the underling mechanism of macrophage on myocardial fibrosis in diabetes.
METHODS
Here, echocardiography was utilized to evaluate cardiac function, and the degree of myocardial fibrosis was assessed using Masson's trichrome staining, followed by single-cell RNA sequencing (scRNA-seq) to analyze the phenotype, function, developmental trajectory, and interactions between immune cells, endothelial cells (ECs), and fibroblasts (FBs) in the hearts of db/db mice at different stages of diabetes. Macrophages and cardiac fibroblasts were also co-cultured in order to study the signaling between macrophages and fibroblasts.
RESULTS
We found that with the development of diabetes mellitus, myocardial hypertrophy and fibrosis occurred that was accompanied by cardiac dysfunction. A significant proportion of immune cells, endothelial cells, and fibroblasts were identified by RNA sequencing. The most significant changes observed were in macrophages, which undergo M1 polarization and are critical for oxidative stress and extracellular matrix (ECM) formation. We further found that M1 macrophages secreted interleukin-1β (IL-1β), which interacted with the receptor on the surface of fibroblasts, to cause myocardial fibrosis. In addition, crosstalk between M1 macrophages and endothelial cells also plays a key role in fibrosis and immune response regulation through IL-1β and corresponding receptors.
CONCLUSIONS
M1 macrophages mediate diabetic myocardial fibrosis through interleukin-1β interaction with fibroblasts.
Topics: Mice; Animals; Interleukin-1beta; Endothelial Cells; Diabetic Cardiomyopathies; Macrophages; Fibrosis; Diabetes Mellitus
PubMed: 38492336
DOI: 10.1016/j.intimp.2024.111858 -
Molecular Medicine Reports May 2024Doxorubicin (Dox) exhibits a high efficacy in the treatment of numerous types of cancer. However, the beneficial cytotoxic effects of Dox are often accompanied by an...
Doxorubicin (Dox) exhibits a high efficacy in the treatment of numerous types of cancer. However, the beneficial cytotoxic effects of Dox are often accompanied by an increase in the risk of cardiotoxicity. Oxidative stress (OS) plays a key role in Dox‑induced cardiomyopathy (DIC). OS in cardiomyocytes disrupts endoplasmic reticulum (ER) function, leading to the accumulation of misfolded/unfolded proteins known as ER stress. ER stress acts as an adaptive mechanism; however, prolonged ER stress together with OS may lead to the initiation of cardiomyocyte apoptosis. The present study aimed to explore the potential of an anti‑diabetic drug, empagliflozin (EMPA), in mitigating Dox‑induced ER stress and cardiomyocyte apoptosis. In the present study, the effects of 1 h pretreatment of EMPA on Dox‑treated cardiomyocytes isolated from Sprague‑Dawley rats were investigated. After 24 h, EMPA pre‑treatment promoted cell survival in the EMPA + Dox group compared with the Dox group. Results of the present study also demonstrated that EMPA mitigated overall ER stress, as the increased expression of ER stress markers was reduced in the EMPA + Dox group. Additionally, OS, inflammation and expression of ER stress apoptotic proteins were also significantly reduced following EMPA pre‑treatment in the EMPA + Dox group. Thus, EMPA may exert beneficial effects on Dox‑induced ER stress and may exhibit potential changes that can be utilised to further evaluate the role of EMPA in mitigating DIC.
Topics: Rats; Animals; Rats, Sprague-Dawley; Cardiomyopathies; Myocytes, Cardiac; Cardiotoxicity; Doxorubicin; Apoptosis; Oxidative Stress; Endoplasmic Reticulum Stress; Benzhydryl Compounds; Glucosides
PubMed: 38488036
DOI: 10.3892/mmr.2024.13198 -
Cardiovascular Diabetology Mar 2024Diabetic cardiomyopathy (DCM) is a major contributor to mortality in diabetic patients, characterized by a multifaceted pathogenesis and limited therapeutic options....
Diabetic cardiomyopathy (DCM) is a major contributor to mortality in diabetic patients, characterized by a multifaceted pathogenesis and limited therapeutic options. While lactate, a byproduct of glycolysis, is known to be significantly elevated in type 2 diabetes, its specific role in DCM remains uncertain. This study reveals an abnormal upregulation of monocarboxylate transporter 4 (MCT4) on the plasma membrane of cardiomyocytes in type 2 diabetes, leading to excessive lactate efflux from these cells. The disruption in lactate transport homeostasis perturbs the intracellular lactate-pyruvate balance in cardiomyocytes, resulting in oxidative stress and inflammatory responses that exacerbate myocardial damage. Additionally, our findings suggest increased lactate efflux augments histone H4K12 lactylation in macrophages, facilitating inflammatory infiltration within the microenvironment. In vivo experiments have demonstrated that inhibiting MCT4 effectively alleviates myocardial oxidative stress and pathological damage, reduces inflammatory macrophage infiltration, and enhances cardiac function in type 2 diabetic mice. Furthermore, a clinical prediction model has been established, demonstrating a notable association between peripheral blood lactate levels and diastolic dysfunction in individuals with type 2 diabetes. This underscores the potential of lactate as a prognostic biomarker for DCM. Ultimately, our findings highlight the pivotal involvement of MCT4 in the dysregulation of cardiac energy metabolism and macrophage-mediated inflammation in type 2 diabetes. These insights offer novel perspectives on the pathogenesis of DCM and pave the way for the development of targeted therapeutic strategies against this debilitating condition.
Topics: Animals; Humans; Mice; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Energy Metabolism; Inflammation; Lactic Acid; Models, Statistical; Prognosis
PubMed: 38486199
DOI: 10.1186/s12933-024-02178-2 -
Cell Stress & Chaperones Apr 2024Long-term hyperglycemia can lead to diabetic cardiomyopathy (DCM), a main lethal complication of diabetes. However, the mechanisms underlying DCM development have not...
Long-term hyperglycemia can lead to diabetic cardiomyopathy (DCM), a main lethal complication of diabetes. However, the mechanisms underlying DCM development have not been fully elucidated. Heat shock protein A12A (HSPA12A) is the atypic member of the Heat shock 70kDa protein family. In the present study, we found that the expression of HSPA12A was upregulated in the hearts of mice with streptozotocin-induced diabetes, while ablation of HSPA12A improved cardiac systolic and diastolic dysfunction and increased cumulative survival of diabetic mice. An increased expression of HSPA12A was also found in H9c2 cardiac cells following treatment with high glucose (HG), while overexpression of HSPA12A-enhanced the HG-induced cardiac cell death, as reflected by higher levels of propidium iodide cells, lactate dehydrogenase leakage, and caspase 3 cleavage. Moreover, the HG-induced increase of oxidative stress, as indicated by dihydroethidium staining, was exaggerated by HSPA12A overexpression. Further studies demonstrated that the HG-induced increases of protein kinase B and forkhead box transcription factors 1 phosphorylation were diminished by HSPA12A overexpression, while pharmacologically inhibition of protein kinase B further enhanced the HG-induced lactate dehydrogenase leakage in HSPA12A overexpressed cardiac cells. Together, the results suggest that hyperglycemia upregulated HSPA12A expression in cardiac cells, by which induced cell death to promote DCM development. Targeting HSPA12A may serve as a potential approach for DCM management.
Topics: Animals; Mice; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Heat-Shock Proteins; Hyperglycemia; Lactate Dehydrogenases; Myocytes, Cardiac; Proto-Oncogene Proteins c-akt; Rats
PubMed: 38485044
DOI: 10.1016/j.cstres.2024.03.004 -
Journal of Molecular and Cellular... Apr 2024Diabetic heart disease morbidity and mortality is escalating. No specific therapeutics exist and mechanistic understanding of diabetic cardiomyopathy etiology is...
Diabetic heart disease morbidity and mortality is escalating. No specific therapeutics exist and mechanistic understanding of diabetic cardiomyopathy etiology is lacking. While lipid accumulation is a recognized cardiomyocyte phenotype of diabetes, less is known about glycolytic fuel handling and storage. Based on in vitro studies, we postulated the operation of an autophagy pathway in the myocardium specific for glycogen homeostasis - glycophagy. Here we visualize occurrence of cardiac glycophagy and show that the diabetic myocardium is characterized by marked glycogen elevation and altered cardiomyocyte glycogen localization. We establish that cardiac glycophagy flux is disturbed in diabetes. Glycophagy may represent a potential therapeutic target for alleviating the myocardial impacts of metabolic disruption in diabetic heart disease.
Topics: Humans; Diabetic Cardiomyopathies; Myocardium; Myocytes, Cardiac; Glycogen; Autophagy; Diabetes Mellitus
PubMed: 38484473
DOI: 10.1016/j.yjmcc.2024.02.009