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Metabolism: Clinical and Experimental Dec 2021Heart failure and cardiovascular disorders represent the leading cause of death in diabetic patients. Here we present a systematic review of the main mechanisms... (Review)
Review
Heart failure and cardiovascular disorders represent the leading cause of death in diabetic patients. Here we present a systematic review of the main mechanisms underlying the development of diabetic cardiomyopathy. We also provide an excursus on the relative contribution of cardiomyocytes, fibroblasts, endothelial and smooth muscle cells to the pathophysiology of heart failure in diabetes. After having described the preclinical tools currently available to dissect the mechanisms of this complex disease, we conclude with a section on the most recent updates of the literature on clinical management.
Topics: Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Heart Failure; Humans
PubMed: 34627874
DOI: 10.1016/j.metabol.2021.154910 -
Frontiers in Endocrinology 2022Diabetes is a chronic metabolic disease that is increasing in prevalence and causes many complications. Diabetic cardiomyopathy (DCM) is a complication of diabetes that... (Review)
Review
Diabetes is a chronic metabolic disease that is increasing in prevalence and causes many complications. Diabetic cardiomyopathy (DCM) is a complication of diabetes that is associated with high mortality, but it is not well defined. Nevertheless, it is generally accepted that DCM refers to a clinical disease that occurs in patients with diabetes and involves ventricular dysfunction, in the absence of other cardiovascular diseases, such as coronary atherosclerotic heart disease, hypertension, or valvular heart disease. However, it is currently uncertain whether the pathogenesis of DCM is directly attributable to metabolic dysfunction or secondary to diabetic microangiopathy. Oxidative stress (OS) is considered to be a key component of its pathogenesis. The production of reactive oxygen species (ROS) in cardiomyocytes is a vicious circle, resulting in further production of ROS, mitochondrial DNA damage, lipid peroxidation, and the post-translational modification of proteins, as well as inflammation, cardiac hypertrophy and fibrosis, ultimately leading to cell death and cardiac dysfunction. ROS have been shown to affect various signaling pathways involved in the development of DCM. For instance, OS causes metabolic disorders by affecting the regulation of PPARα, AMPK/mTOR, and SIRT3/FOXO3a. Furthermore, OS participates in inflammation mediated by the NF-κB pathway, NLRP3 inflammasome, and the TLR4 pathway. OS also promotes TGF-β-, Rho-ROCK-, and Notch-mediated cardiac remodeling, and is involved in the regulation of calcium homeostasis, which impairs ATP production and causes ROS overproduction. In this review, we summarize the signaling pathways that link OS to DCM, with the intention of identifying appropriate targets and new antioxidant therapies for DCM.
Topics: Diabetes Mellitus; Diabetic Cardiomyopathies; Humans; Inflammation; Myocytes, Cardiac; Oxidative Stress; Reactive Oxygen Species; Signal Transduction
PubMed: 35784531
DOI: 10.3389/fendo.2022.907757 -
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 -
Oxidative Medicine and Cellular... 2021The mitochondrial dynamics and mitochondrial biogenesis are essential for maintaining the bioenergy function of mitochondria in diabetic cardiomyopathy (DCM). Previous...
BACKGROUND
The mitochondrial dynamics and mitochondrial biogenesis are essential for maintaining the bioenergy function of mitochondria in diabetic cardiomyopathy (DCM). Previous studies have revealed that secreted frizzled-related protein 2 (SFRP2) is beneficial against apoptosis and oxidative stress. However, no research has confirmed whether SFRP2 regulates oxidative stress and apoptosis through mitochondrial function in DCM.
METHODS
Exposure of H9C2 cardiomyocytes in high glucose (HG) 25 mM and palmitic acid (PAL) 0.2 mM was used to simulate DCM . H9C2 cells with SFRP2 overexpression or SFRP2 knockdown were constructed and cultured under glucolipotoxicity or normal glucose conditions. An SD rat model of type 2 diabetes mellitus (T2DM) was generated using a high-fat diet combined with a low-dose STZ injection. Overexpression of SFRP2 in the rat model was generated by using an adeno-associated virus approach. CCK-8, TUNEL assay, and DHE staining were used to detect cell viability, and MitoTracker Red CMXRos was used to detect changes in mitochondrial membrane potential. We used qRT-PCR and western blot to further explore the mechanisms of SFRP2 regulating mitochondrial dynamics through the AMPK/PGC1- pathway to improve diabetic cardiomyocyte injury.
RESULTS
Our results indicated that SFRP2 was significantly downregulated in H9C2 cells and cardiac tissues in T2DM conditions, accompanied by decreased expression of mitochondrial dysfunction. The mitochondrial membrane potential was reduced, and the cells were led to oxidative stress injury and apoptosis. Furthermore, the overexpression of SFRP2 could reverse apoptosis and promote mitochondrial function in T2DM conditions and . We also found that silencing endogenous SFRP2 could further promote glucolipotoxicity-induced mitochondrial dysfunction and apoptosis in cardiomyocytes, accompanied by downregulation of p-AMPK.
CONCLUSION
SFRP2 exerted cardioprotective effects by salvaging mitochondrial function in an AMPK-PGC1-dependent manner, which modulates mitochondrial dynamics and mitochondrial biogenesis, reducing oxidative stress and apoptosis. SFRP2 may be a promising therapeutic biomarker in DCM.
Topics: Animals; Apoptosis; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Diet, High-Fat; Male; Membrane Potential, Mitochondrial; Membrane Proteins; Mitochondrial Dynamics; Myocytes, Cardiac; Organelle Biogenesis; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species
PubMed: 34790288
DOI: 10.1155/2021/9265016 -
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 -
Experimental & Molecular Medicine Apr 2023Dipeptidyl peptidase-4 (DPP-4) inhibitors are glucose-lowering drugs for type 2 diabetes mellitus (T2DM). We investigated whether evogliptin® (EVO), a DPP-4 inhibitor,...
Dipeptidyl peptidase-4 (DPP-4) inhibitors are glucose-lowering drugs for type 2 diabetes mellitus (T2DM). We investigated whether evogliptin® (EVO), a DPP-4 inhibitor, could protect against diabetic cardiomyopathy (DCM) and the underlying mechanisms. Eight-week-old diabetic and obese db/db mice were administered EVO (100 mg/kg/day) daily by oral gavage for 12 weeks. db/db control mice and C57BLKS/J as wild-type (WT) mice received equal amounts of the vehicle. In addition to the hypoglycemic effect, we examined the improvement in cardiac contraction/relaxation ability, cardiac fibrosis, and myocardial hypertrophy by EVO treatment. To identify the mechanisms underlying the improvement in diabetic cardiomyopathy by EVO treatment, its effect on lipotoxicity and the mitochondrial damage caused by lipid droplet accumulation in the myocardium were analyzed. EVO lowered the blood glucose and HbA1c levels and improved insulin sensitivity but did not affect the body weight or blood lipid profile. Cardiac systolic/diastolic function, hypertrophy, and fibrosis were improved in the EVO-treated group. EVO prevented cardiac lipotoxicity by reducing the accumulation of lipid droplets in the myocardium through suppression of CD36, ACSL1, FABP3, PPARgamma, and DGAT1 and enhancement of the phosphorylation of FOXO1, indicating its inhibition. The EVO-mediated improvement in mitochondrial function and reduction in damage were achieved through activation of PGC1a/NRF1/TFAM, which activates mitochondrial biogenesis. RNA-seq results for the whole heart confirmed that EVO treatment mainly affected the differentially expressed genes (DEGs) related to lipid metabolism. Collectively, these findings demonstrate that EVO improves cardiac function by reducing lipotoxicity and mitochondrial injury and provides a potential therapeutic option for DCM.
Topics: Mice; Animals; Diabetic Cardiomyopathies; Dipeptidyl-Peptidase IV Inhibitors; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Cardiomegaly
PubMed: 37009790
DOI: 10.1038/s12276-023-00958-6 -
Circulation Research Nov 2020Diabetic heart disease (DHD) is a debilitating manifestation of type 2 diabetes mellitus. Exercise has been proposed as a potential therapy for DHD, although the...
RATIONALE
Diabetic heart disease (DHD) is a debilitating manifestation of type 2 diabetes mellitus. Exercise has been proposed as a potential therapy for DHD, although the effectiveness of exercise in preventing or reversing the progression of DHD remains controversial. Cardiac function is critically dependent on the preservation of coronary vascular function.
OBJECTIVE
We aimed to elucidate the effectiveness and mechanisms by which exercise facilitates coronary and cardiac-protection during the onset and progression of DHD.
METHODS AND RESULTS
Diabetic db/db and nondiabetic mice, with or without underlying cardiac dysfunction (16 and 8 weeks old, respectively) were subjected to either moderate-intensity exercise or high-intensity exercise for 8 weeks. Subsequently, synchrotron microangiography, immunohistochemistry, Western blot, and real-time polymerase chain reaction were used to assess time-dependent changes in cardiac and coronary structure and function associated with diabetes mellitus and exercise and determine whether these changes reflect the observed changes in cardiac-enriched and vascular-enriched microRNAs (miRNAs). We show that, if exercise is initiated from 8 weeks of age, both moderate-intensity exercise and high-intensity exercise prevented the onset of coronary and cardiac dysfunction, apoptosis, fibrosis, microvascular rarefaction, and disruption of miRNA signaling, as seen in the nonexercised diabetic mice. Conversely, the cardiovascular benefits of moderate-intensity exercise were absent if the exercise was initiated after the diabetic mice had already established cardiac dysfunction (ie, from 16 weeks of age). The experimental silencing or upregulation of miRNA-126 activity suggests the mechanism underpinning the cardiovascular benefits of exercise were mediated, at least in part, through tissue-specific miRNAs.
CONCLUSIONS
Our findings provide the first experimental evidence for the critical importance of early exercise intervention in ameliorating the onset and progression of DHD. Our results also suggest that the beneficial effects of exercise are mediated through the normalization of cardiovascular-enriched miRNAs, which are dysregulated in DHD.
Topics: Animals; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Disease Models, Animal; Exercise Therapy; Female; Fibrosis; Gene Expression Regulation; Male; Mice; MicroRNAs; Myocardium; Physical Conditioning, Animal; Running; Signal Transduction; Time Factors; Ventricular Function, Left; Ventricular Remodeling
PubMed: 32907486
DOI: 10.1161/CIRCRESAHA.120.317604 -
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 -
Journal of Cardiac Failure Dec 2010Individuals with diabetes are at a significantly greater risk of developing cardioymyopathy and heart failure despite adjusting for concomitant risks such as coronary... (Review)
Review
Individuals with diabetes are at a significantly greater risk of developing cardioymyopathy and heart failure despite adjusting for concomitant risks such as coronary artery disease or hypertension. This has led to the increased recognition of a distinct disease process termed as "diabetic cardiomyopathy." In this article, we perform an extensive review of the pathogenesis and treatment of this disease. From a clinical perspective, physicians should be aware of this entity, and early screening should be considered because physical evidence of early diabetic cardiomyopathy could be difficult to detect. Early detection of the disease should prompt intensification of glycemic control, concomitant risk factors, use of pharmacologic agents such as β-blockers and renin-angiotensin-aldosterone system antagosists. From a research perspective, more studies on myocardial tissue from diabetic patients are needed. Clinical trials to evaluate the development of diabetic cardiomyopathy and fibrosis in early stages of the disease, as well as clinical trials of pharmacologic intervention in patients specifically with diabetic cardiomyopathy, need to be conducted.
Topics: Animals; Cardiomyopathies; Diabetes Mellitus; Diabetic Cardiomyopathies; Heart Failure; Humans; Hyperglycemia
PubMed: 21111987
DOI: 10.1016/j.cardfail.2010.07.249 -
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