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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 -
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 -
Advances in Experimental Medicine and... 2023Differential gene expression is associated with diabetic cardiomyopathy (DMCM) and culminates in adverse remodeling in the diabetic heart. Genome editing is a technology...
Differential gene expression is associated with diabetic cardiomyopathy (DMCM) and culminates in adverse remodeling in the diabetic heart. Genome editing is a technology utilized to alter endogenous genes. Genome editing also provides an option to induce cardioprotective genes or inhibit genes linked to adverse cardiac remodeling and thus has promise in ameliorating DMCM. Non-coding genes have emerged as novel regulators of cellular signaling and may serve as potential therapeutic targets for DMCM. Specifically, there is a widespread change in the gene expression of fetal cardiac genes and microRNAs, termed genetic reprogramming, that promotes pathological remodeling and contributes to heart failure in diabetes. This genetic reprogramming of both coding and non-coding genes varies with the progression and severity of DMCM. Thus, genetic editing provides a promising option to investigate the role of specific genes/non-coding RNAs in DMCM initiation and progression as well as developing therapeutics to mitigate cardiac remodeling and ameliorate DMCM. This chapter will summarize the research progress in genome editing and DMCM and provide future directions for utilizing genome editing as an approach to prevent and/or treat DMCM.
Topics: Humans; Diabetic Cardiomyopathies; Gene Editing; Ventricular Remodeling; Heart; Heart Failure; Diabetes Mellitus
PubMed: 36454462
DOI: 10.1007/978-981-19-5642-3_7 -
Acta Physiologica (Oxford, England) Mar 2020Obesity-induced insulin resistance and type 2 diabetes mellitus can ultimately result in various complications, including diabetic cardiomyopathy. In this case, cardiac... (Review)
Review
Obesity-induced insulin resistance and type 2 diabetes mellitus can ultimately result in various complications, including diabetic cardiomyopathy. In this case, cardiac dysfunction is characterized by metabolic disturbances such as impaired glucose oxidation and an increased reliance on fatty acid (FA) oxidation. Mitochondrial dysfunction has often been associated with the altered metabolic function in the diabetic heart, and may result from FA-induced lipotoxicity and uncoupling of oxidative phosphorylation. In this review, we address the metabolic changes in the diabetic heart, focusing on the loss of metabolic flexibility and cardiac mitochondrial function. We consider the alterations observed in mitochondrial substrate utilization, bioenergetics and dynamics, and highlight new areas of research which may improve our understanding of the cause and effect of cardiac mitochondrial dysfunction in diabetes. Finally, we explore how lifestyle (nutrition and exercise) and pharmacological interventions can prevent and treat metabolic and mitochondrial dysfunction in diabetes.
Topics: Animals; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Fatty Acids; Humans; Insulin Resistance; Mitochondria, Heart
PubMed: 31840389
DOI: 10.1111/apha.13430 -
Circulation Research Mar 2021In diabetic patients, heart failure with predominant left ventricular (LV) diastolic dysfunction is a common complication for which there is no effective treatment....
RATIONALE
In diabetic patients, heart failure with predominant left ventricular (LV) diastolic dysfunction is a common complication for which there is no effective treatment. Oxidation of the NOS (nitric oxide synthase) cofactor tetrahydrobiopterin (BH4) and dysfunctional NOS activity have been implicated in the pathogenesis of the diabetic vascular and cardiomyopathic phenotype.
OBJECTIVE
Using mice models and human myocardial samples, we evaluated whether and by which mechanism increasing myocardial BH4 availability prevented or reversed LV dysfunction induced by diabetes.
METHODS AND RESULTS
In contrast to the vascular endothelium, BH4 levels, superoxide production, and NOS activity (by liquid chromatography) did not differ in the LV myocardium of diabetic mice or in atrial tissue from diabetic patients. Nevertheless, the impairment in both cardiomyocyte relaxation and [Ca]i (intracellular calcium) decay and in vivo LV function (echocardiography and tissue Doppler) that developed in wild-type mice 12 weeks post-diabetes induction (streptozotocin, 42-45 mg/kg) was prevented in mGCH1-Tg (mice with elevated myocardial BH4 content secondary to trangenic overexpression of GTP-cyclohydrolase 1) and reversed in wild-type mice receiving oral BH4 supplementation from the 12th to the 18th week after diabetes induction. The protective effect of BH4 was abolished by CRISPR/Cas9-mediated knockout of nNOS (the neuronal NOS isoform) in mGCH1-Tg. In HEK (human embryonic kidney) cells, S-nitrosoglutathione led to a PKG (protein kinase G)-dependent increase in plasmalemmal density of the insulin-independent glucose transporter GLUT-1 (glucose transporter-1). In cardiomyocytes, mGCH1 overexpression induced a NO/sGC (soluble guanylate cyclase)/PKG-dependent increase in glucose uptake via GLUT-1, which was instrumental in preserving mitochondrial creatine kinase activity, oxygen consumption rate, LV energetics (by phosphorous magnetic resonance spectroscopy), and myocardial function.
CONCLUSIONS
We uncovered a novel mechanism whereby myocardial BH4 prevents and reverses LV diastolic and systolic dysfunction associated with diabetes via an nNOS-mediated increase in insulin-independent myocardial glucose uptake and utilization. These findings highlight the potential of GCH1/BH4-based therapeutics in human diabetic cardiomyopathy. Graphic Abstract: A graphic abstract is available for this article.
Topics: Animals; Biopterins; Diabetic Cardiomyopathies; GTP Cyclohydrolase; Glucose; Glucose Transporter Type 1; Glutathione; HEK293 Cells; Humans; Mice; Mice, Inbred C57BL; Myocytes, Cardiac; Nitric Oxide Synthase Type I; Ventricular Dysfunction, Left
PubMed: 33494625
DOI: 10.1161/CIRCRESAHA.120.316656 -
Phytomedicine : International Journal... Oct 2023Hyperglycemic induced cardiac hypertrophy and cardiac inflammation are important pathological processes in diabetic cardiomyopathy. β-elemene (Ele) is a natural...
BACKGROUND
Hyperglycemic induced cardiac hypertrophy and cardiac inflammation are important pathological processes in diabetic cardiomyopathy. β-elemene (Ele) is a natural compound extracted from Curcuma Rhizoma and has anti-tumor effects. It also has therapeutic effects in some inflammatory diseases. However, the therapeutic effect of Ele on diabetic cardiomyopathy is not clear. The purpose of this study was to evaluate the effect of Ele on hyperglycemia-caused cardiac remodeling and heart failure.
METHODS
C57BL/6 mice were intraperitoneally injected with streptozotocin to induce DCM, and Ele was administered intragastric after 8 weeks to investigate the effect of Ele. RNA sequencing of cardiac tissue was performed to investigate the mechanism.
RESULTS
Ele markedly inhibited cardiac inflammation, fibrosis and hypertrophy in diabetic mice, as well as in high glucose-induced cardiomyocytes. RNA sequencing showed that cardioprotective effect of Ele involved the JAK/STAT3-NF-κB signaling pathway. Ele alleviated heart and cardiomyocyte inflammation in mice by blocking diabetes-induced JAK2 and STAT3 phosphorylation and NF-κB activation.
CONCLUSIONS
The study found that Ele preserved the hearts of diabetic mice by inhibiting JAK/STAT3 and NF-κB mediated inflammatory responses, suggesting that Ele is an effective therapy for DCM.
Topics: Mice; Animals; NF-kappa B; Diabetic Cardiomyopathies; Diabetes Mellitus, Experimental; Mice, Inbred C57BL; Hyperglycemia; Myocytes, Cardiac; Inflammation
PubMed: 37531901
DOI: 10.1016/j.phymed.2023.154987 -
Cardiovascular Diabetology Aug 2023Myocardial microvascular injury is the key event in early diabetic heart disease. The injury of myocardial microvascular endothelial cells (CMECs) is the main cause and...
BACKGROUND
Myocardial microvascular injury is the key event in early diabetic heart disease. The injury of myocardial microvascular endothelial cells (CMECs) is the main cause and trigger of myocardial microvascular disease. Mitochondrial calcium homeostasis plays an important role in maintaining the normal function, survival and death of endothelial cells. Considering that mitochondrial calcium uptake 1 (MICU1) is a key molecule in mitochondrial calcium regulation, this study aimed to investigate the role of MICU1 in CMECs and explore its underlying mechanisms.
METHODS
To examine the role of endothelial MICU1 in diabetic cardiomyopathy (DCM), we used endothelial-specific MICU1 mice to establish a diabetic mouse model and evaluate the cardiac function. In addition, MICU1 overexpression was conducted by injecting adeno-associated virus 9 carrying MICU1 (AAV9-MICU1). Transcriptome sequencing technology was used to explore underlying molecular mechanisms.
RESULTS
Here, we found that MICU1 expression is decreased in CMECs of diabetic mice. Moreover, we demonstrated that endothelial cell MICU1 knockout exacerbated the levels of cardiac hypertrophy and interstitial myocardial fibrosis and led to a further reduction in left ventricular function in diabetic mice. Notably, we found that AAV9-MICU1 specifically upregulated the expression of MICU1 in CMECs of diabetic mice, which inhibited nitrification stress, inflammatory reaction, and apoptosis of the CMECs, ameliorated myocardial hypertrophy and fibrosis, and promoted cardiac function. Further mechanistic analysis suggested that MICU1 deficiency result in excessive mitochondrial calcium uptake and homeostasis imbalance which caused nitrification stress-induced endothelial damage and inflammation that disrupted myocardial microvascular endothelial barrier function and ultimately promoted DCM progression.
CONCLUSIONS
Our findings demonstrate that MICU1 expression was downregulated in the CMECs of diabetic mice. Overexpression of endothelial MICU1 reduced nitrification stress induced apoptosis and inflammation by inhibiting mitochondrial calcium uptake, which improved myocardial microvascular function and inhibited DCM progression. Our findings suggest that endothelial MICU1 is a molecular intervention target for the potential treatment of DCM.
Topics: Animals; Mice; Calcium; Calcium-Binding Proteins; Dependovirus; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Endothelial Cells; Inflammation; Mitochondrial Membrane Transport Proteins
PubMed: 37592255
DOI: 10.1186/s12933-023-01941-1 -
Current Diabetes Reviews 2024Diabetic cardiomyopathy (DCM) is a myocardial disorder that is characterised by structural and functional abnormalities of the heart muscle in the absence of... (Review)
Review
Diabetic cardiomyopathy (DCM) is a myocardial disorder that is characterised by structural and functional abnormalities of the heart muscle in the absence of hypertension, valvular heart disease, congenital heart defects, or coronary artery disease (CAD). After witnessing a particular form of cardiomyopathy in diabetic individuals, Rubler . came up with the moniker diabetic cardiomyopathy in 1972. Four stages of DCM are documented, and the American College of Cardiology/American Heart Association Stage and New York Heart Association Class for HF have some overlap. Diabetes is linked to several distinct forms of heart failure. Around 40% of people with heart failure with preserved ejection fraction (HFpEF) have diabetes, which is thought to be closely associated with the pathophysiology of HFpEF. Diabetes and HF are uniquely associated in a bidirectional manner. When compared to the general population without diabetes, those with diabetes have a risk of heart failure that is up to four times higher. A biomarker is a trait that is reliably measured and assessed as a predictor of healthy biological activities, pathological processes, or pharmacologic responses to a clinical treatment. Several biomarker values have been discovered to be greater in patients with diabetes than in control subjects among those who have recently developed heart failure. Myocardial fibrosis and hypertrophy are the primary characteristics of DCM, and structural alterations in the diabetic myocardium are often examined by non-invasive, reliable, and reproducible procedures. An invasive method called endomyocardial biopsy (EMB) is most often used to diagnose many cardiac illnesses.
Topics: Diabetic Cardiomyopathies; Humans; Heart Failure; Myocardium; Biomarkers
PubMed: 37842898
DOI: 10.2174/0115733998255538231001122639 -
Cells Jan 2022The incidence and prevalence of diabetes mellitus (DM) are increasing worldwide, and the resulting cardiac complications are the leading cause of death. Among these... (Review)
Review
The incidence and prevalence of diabetes mellitus (DM) are increasing worldwide, and the resulting cardiac complications are the leading cause of death. Among these complications is diabetes-induced cardiomyopathy (DCM), which is the consequence of a pro-inflammatory condition, oxidative stress and fibrosis caused by hyperglycemia. Cardiac remodeling will lead to an imbalance in cell survival and death, which can promote cardiac dysfunction. Since the conventional treatment of DM generally does not address the prevention of cardiac remodeling, it is important to develop new alternatives for the treatment of cardiovascular complications induced by DM. Thus, therapy with mesenchymal stem cells has been shown to be a promising approach for the prevention of DCM because of their anti-apoptotic, anti-fibrotic and anti-inflammatory effects, which could improve cardiac function in patients with DM.
Topics: Animals; Clinical Trials as Topic; Diabetic Cardiomyopathies; Epigenesis, Genetic; Humans; Mesenchymal Stem Cell Transplantation; Models, Biological; Vascular Remodeling
PubMed: 35053356
DOI: 10.3390/cells11020240 -
Cardiovascular Research Feb 2022Diabetes mellitus increases the risk of developing heart failure, and the co-existence of both diseases worsens cardiovascular outcomes, hospitalization, and the... (Review)
Review
Diabetes mellitus increases the risk of developing heart failure, and the co-existence of both diseases worsens cardiovascular outcomes, hospitalization, and the progression of heart failure. Despite current advancements on therapeutic strategies to manage hyperglycaemia, the likelihood of developing diabetes-induced heart failure is still significant, especially with the accelerating global prevalence of diabetes and an ageing population. This raises the likelihood of other contributing mechanisms beyond hyperglycaemia in predisposing diabetic patients to cardiovascular disease risk. There has been considerable interest in understanding the alterations in cardiac structure and function in diabetic patients, collectively termed as 'diabetic cardiomyopathy'. However, the factors that contribute to the development of diabetic cardiomyopathies are not fully understood. This review summarizes the main characteristics of diabetic cardiomyopathies, and the basic mechanisms that contribute to its occurrence. This includes perturbations in insulin resistance, fuel preference, reactive oxygen species generation, inflammation, cell death pathways, neurohormonal mechanisms, advanced glycated end-products accumulation, lipotoxicity, glucotoxicity, and post-translational modifications in the heart of the diabetic. This review also discusses the impact of antihyperglycaemic therapies on the development of heart failure, as well as how current heart failure therapies influence glycaemic control in diabetic patients. We also highlight the current knowledge gaps in understanding how diabetes induces heart failure.
Topics: Diabetes Mellitus; Diabetic Cardiomyopathies; Heart; Heart Failure; Humans; Hypoglycemic Agents; Insulin Resistance
PubMed: 33783483
DOI: 10.1093/cvr/cvab120