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Diabetes & Vascular Disease Research Jul 2015Type 2 diabetes mellitus escalates the risk of heart failure partly via its ability to induce a cardiomyopathic state that is independent of coronary artery disease and... (Review)
Review
Type 2 diabetes mellitus escalates the risk of heart failure partly via its ability to induce a cardiomyopathic state that is independent of coronary artery disease and hypertension. Although the pathogenesis of diabetic cardiomyopathy has yet to be fully elucidated, aberrations in cardiac substrate metabolism and energetics are thought to be key drivers. These aberrations include excessive fatty acid utilisation and storage, suppressed glucose oxidation and impaired mitochondrial oxidative phosphorylation. An appreciation of how these abnormalities arise and synergise to promote adverse cardiac remodelling is critical to their effective amelioration. This review focuses on disturbances in myocardial fuel (fatty acids and glucose) flux and energetics in type 2 diabetes, how these disturbances relate to the development of diabetic cardiomyopathy and the potential therapeutic agents that could be used to correct them.
Topics: Antioxidants; Cardiovascular Agents; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Energy Metabolism; Fatty Acids; Glucose; Humans; Mitochondria, Heart; Myocardium; Organophosphorus Compounds; Oxidative Phosphorylation; Oxidative Stress; Perhexiline; Ranolazine; Trimetazidine; Ubiquinone
PubMed: 25941161
DOI: 10.1177/1479164115580936 -
International Journal of Molecular... Nov 2023Ginsenoside Rg3 extracted from has therapeutic effects on diabetes and heart diseases. However, the underlying mechanism of ginsenoside Rg3 on diabetic cardiomyopathy...
Ginsenoside Rg3 extracted from has therapeutic effects on diabetes and heart diseases. However, the underlying mechanism of ginsenoside Rg3 on diabetic cardiomyopathy (DCM) remains unclear. 24-week-old diabetic db/db mice were treated with ginsenoside Rg3 for 12 weeks, then body weight, serum lipids, adiponectin levels, as well as cardiac function and pathological morphology, were measured. The targets of ginsenoside Rg3 and its regulation of the adiponectin pathway were also evaluated on 3T3-L1 or H9c2 cells. Ginsenoside Rg3 directly bound to PPAR-γ, improving adiponectin secretion and promoting adiponectin signaling. Significantly attenuated overweight, hyperglycemia, and hyperlipidemia, as well as alleviated lipid accumulation and dysfunction in adipose, liver, and heart tissues, were observed in the ginsenoside Rg3-treated group. Ginsenoside Rg3 could be a promising drug targeting PPAR-γ to treat diabetic cardiomyopathy.
Topics: Animals; Mice; Adiponectin; Diabetes Mellitus; Diabetic Cardiomyopathies; Ginsenosides; PPAR gamma; Signal Transduction
PubMed: 38069059
DOI: 10.3390/ijms242316736 -
Biology Direct Nov 2022Cardiac fibrosis is a leading cause of cardiac dysfunction in patients with diabetes. However, the underlying mechanisms of cardiac fibrosis remain unclear. This study...
BACKGROUND
Cardiac fibrosis is a leading cause of cardiac dysfunction in patients with diabetes. However, the underlying mechanisms of cardiac fibrosis remain unclear. This study aimed to investigate the role of the long non-coding RNA (LncRNA) Airn in the pathogenesis of cardiac fibrosis in diabetic cardiomyopathy (DCM) and its underlying mechanism.
METHODS
Diabetes mellitus (DM) was induced in mice by streptozotocin injection. An intramyocardial adeno-associated virus (AAV) was used to manipulate Airn expression. The functional significance and underlying mechanisms in DCM fibrosis were investigated both in vitro and in vivo.
RESULTS
Diabetic hearts showed a significant impairment in cardiac function, accompanied by obviously increased cardiac fibrosis. Interestingly, lncRNA Airn expression was significantly decreased in both diabetic hearts and high glucose (HG)-treated cardiac fibroblasts (CFs). AAV-mediated Airn reconstitution prevented cardiac fibrosis and the development of DCM, while Airn knockdown induced cardiac fibrosis phenotyping DCM. As in vitro, Airn reversed HG-induced fibroblast-myofibroblast transition, aberrant CFs proliferation and section of collagen I. In contrast, Airn knockdown mimicked a HG-induced CFs phenotype. Mechanistically, we identified that Airn exerts anti-fibrotic effects by directly binding to insulin-like growth factor 2 mRNA-binding protein 2 (IMP2) and further prevents its ubiquitination-dependent degradation. Moreover, we revealed that Airn/IMP2 protected p53 mRNA from degradation in m6A manner, leading to CF cell cycle arrest and reduced cardiac fibrosis. As a result, ablation of p53 blunted the inhibitory effects of Airn on fibroblast activation and cardiac fibrosis.
CONCLUSIONS
Our study demonstrated for the first time that Airn prevented the development of cardiac fibrosis in diabetic heart via IMP2-p53 axis in an m6A dependent manner. LncRNA Airn could be a promising therapeutic target for cardiac fibrosis in DCM.
Topics: Animals; Mice; Diabetes Mellitus; Diabetic Cardiomyopathies; Fibroblasts; Fibrosis; RNA, Long Noncoding; RNA, Messenger; Tumor Suppressor Protein p53; RNA-Binding Proteins
PubMed: 36384975
DOI: 10.1186/s13062-022-00346-6 -
Biomedicine & Pharmacotherapy =... Jan 2019Cardiovascular complications are considered one of the leading causes of morbidity and mortality among diabetic patients. Diabetic cardiomyopathy (DCM) is a type of... (Review)
Review
Cardiovascular complications are considered one of the leading causes of morbidity and mortality among diabetic patients. Diabetic cardiomyopathy (DCM) is a type of cardiovascular damage presents in diabetic patients independent of the coexistence of ischemic heart disease or hypertension. It is characterized by impaired diastolic relaxation time, myocardial dilatation and hypertrophy and reduced systolic and diastolic functions of the left ventricle. Molecular mechanisms underlying these pathological changes in the diabetic heart are most likely multifactorial and include, but not limited to, oxidative/nitrosative stress, increased advanced glycation end products, mitochondrial dysfunction, inflammation and cell death. The aim of this review is to address the major molecular mechanisms implicated in the pathogenesis of DCM. In addition, this review provides studies conducted to determine the pharmacological effects of (-)-epigallocatechin-3-gallate (EGCG), the major polyphenol in green tea, focusing on its therapeutic potential against the processes involved in the pathogenesis and progression of DCM. EGCG has been shown to exert several potential therapeutic properties both in vitro and in vivo. Given its therapeutic potential, EGCG might be a promising drug candidate to decrease the morbidity and mortality associated with DCM and other diabetes complications.
Topics: Animals; Antioxidants; Catechin; Diabetic Cardiomyopathies; Humans; Oxidative Stress; Polyphenols; Tea
PubMed: 30551473
DOI: 10.1016/j.biopha.2018.11.086 -
Circulation Research May 2020The term diabetic cardiomyopathy is defined as the presence of abnormalities in myocardial structure and function that occur in the absence of, or in addition to,... (Review)
Review
The term diabetic cardiomyopathy is defined as the presence of abnormalities in myocardial structure and function that occur in the absence of, or in addition to, well-established cardiovascular risk factors. A key contributor to this abnormal structural-functional relation is the complex interplay of myocardial metabolic remodeling, defined as the loss the flexibility in myocardial substrate metabolism and its downstream detrimental effects, such as mitochondrial dysfunction, inflammation, and fibrosis. In parallel with the growth in understanding of these biological underpinnings has been developmental advances in imaging tools such as positron emission tomography and magnetic resonance imaging and spectroscopy that permit the detection and in many cases quantification, of the processes that typifies the myocardial metabolic remodeling in diabetic cardiomyopathy. The imaging readouts can be obtained in both preclinical models of diabetes mellitus and patients with diabetes mellitus facilitating the bi-directional movement of information between bench and bedside. Moreover, imaging biomarkers provided by these tools are now being used to enhance discovery and development of therapies designed to reduce the myocardial effects of diabetes mellitus through metabolic modulation. In this review, the use of these imaging tools in the patient with diabetes mellitus from a mechanistic, therapeutic effect, and clinical management perspective will be discussed.
Topics: Animals; Diabetic Cardiomyopathies; Energy Metabolism; Fibrosis; Humans; Inflammation; Magnetic Resonance Imaging; Positron-Emission Tomography
PubMed: 32437305
DOI: 10.1161/CIRCRESAHA.120.315899 -
International Journal of Molecular... Dec 2021Diabetic cardiomyopathy (DCM), as a common complication of diabetes, is characterized by chronic low-grade inflammation. The NLRP3 inflammasome is a key sensor mediating... (Review)
Review
Diabetic cardiomyopathy (DCM), as a common complication of diabetes, is characterized by chronic low-grade inflammation. The NLRP3 inflammasome is a key sensor mediating innate immune and inflammatory responses. However, the mechanisms initiating and promoting NLRP3 inflammasome activation in DCM is largely unexplored. The aim of the present review is to describe the link between NLRP3 inflammasome and DCM, and to provide evidence highlighting the importance of exercise training in DCM intervention. Collectively, this evidence suggests that DCM is an inflammatory disease aggravated by NLRP3 inflammasome-mediated release of IL-1β and IL-18. In addition, chronic exercise intervention is an effective preventive and therapeutic method to alleviate DCM via modulating the NLRP3 inflammasome.
Topics: Diabetic Cardiomyopathies; Exercise Therapy; Gene Expression Regulation; Humans; Interleukin-18; Interleukin-1beta; NLR Family, Pyrin Domain-Containing 3 Protein; Treatment Outcome
PubMed: 34948026
DOI: 10.3390/ijms222413228 -
Biochimica Et Biophysica Acta.... May 2018MG53 is a member of tripartite motif family (TRIM) that expressed most abundantly in striated muscle. Using rodent models, many studies have demonstrated the MG53 not... (Review)
Review
MG53 is a member of tripartite motif family (TRIM) that expressed most abundantly in striated muscle. Using rodent models, many studies have demonstrated the MG53 not only facilitates membrane repair after ischemia reperfusion injury, but also contributes to the protective effects of both pre- and post-conditioning. Recently, however, it has been shown that MG53 participates in the regulation of many metabolic processes, especially insulin signaling pathway. Thus, sustained overexpression of MG53 may contribute to the development of various metabolic disorders in striated muscle. In this review, using cardiac muscle as an example, we will discuss muscle metabolic disturbances associated with diabetes and the current understanding of the underlying molecular mechanisms; in particular, the pathogenesis of diabetic cardiomyopathy. We will focus on the pathways that MG53 regulates and how the dysregulation of MG53 leads to metabolic disorders, thereby establishing a causal relationship between sustained upregulation of MG53 and the development of muscle insulin resistance and metabolic disorders. This article is part of a Special issue entitled Cardiac adaptations to obesity, diabetes and insulin resistance, edited by Professors Jan F.C. Glatz, Jason R.B. Dyck and Christine Des Rosiers.
Topics: Animals; Blood Glucose; Carrier Proteins; Diabetes Mellitus; Diabetic Cardiomyopathies; Energy Metabolism; Humans; Insulin; Insulin Resistance; Metabolic Syndrome; Myocardium; Signal Transduction; Tripartite Motif Proteins
PubMed: 29017896
DOI: 10.1016/j.bbadis.2017.10.013 -
Cell Stress & Chaperones Nov 2023Diabetic cardiomyopathy describes decreased myocardial function in diabetic patients in the absence of other heart diseases such as myocardial ischemia and hypertension.... (Review)
Review
Diabetic cardiomyopathy describes decreased myocardial function in diabetic patients in the absence of other heart diseases such as myocardial ischemia and hypertension. Recent studies have defined numerous molecular interactions and signaling events that may account for deleterious changes in mitochondrial dynamics and functions influenced by hyperglycemic stress. A metabolic switch from glucose to fatty acid oxidation to fuel ATP synthesis, mitochondrial oxidative injury resulting from increased mitochondrial ROS production and decreased antioxidant capacity, enhanced mitochondrial fission and defective mitochondrial fusion, impaired mitophagy, and blunted mitochondrial biogenesis are major signatures of mitochondrial pathologies during diabetic cardiomyopathy. This review describes the molecular alterations underlying mitochondrial abnormalities associated with hyperglycemia and discusses their influence on cardiomyocyte viability and function. Based on basic research findings and clinical evidence, diabetic treatment standards and their impact on mitochondrial function, as well as mitochondria-targeted therapies of potential benefit for diabetic cardiomyopathy patients, are also summarized.
Topics: Humans; Diabetic Cardiomyopathies; Mitochondria; Myocytes, Cardiac; Myocardial Ischemia; Cardiovascular Diseases; Mitochondrial Dynamics; Diabetes Mellitus
PubMed: 37405612
DOI: 10.1007/s12192-023-01361-w -
Biochimica Et Biophysica Acta.... Jan 2021Diabetes mellitus-induced heart disease, including diabetic cardiomyopathy, is an important medical problem and is difficult to treat. Diabetes mellitus increases the... (Review)
Review
Diabetes mellitus-induced heart disease, including diabetic cardiomyopathy, is an important medical problem and is difficult to treat. Diabetes mellitus increases the risk for heart failure and decreases cardiac myocyte function, which are linked to changes in cardiac mitochondrial energy metabolism. The free mitochondrial calcium concentration ([Ca]) is fundamental in activating the mitochondrial respiratory chain complexes and ATP production and is also known to regulate the activity of key mitochondrial dehydrogenases. The mitochondrial calcium uniporter complex (MCUC) plays a major role in mediating mitochondrial Ca import, and its expression and function therefore may have a marked impact on cardiac myocyte metabolism and function. Here, we summarize the pathophysiological role of [Ca] handling and MCUC in the diabetic heart. In addition, we evaluate potential therapeutic targets, directed to the machinery that regulates mitochondrial calcium handling, to alleviate diabetes-related cardiac disease.
Topics: Calcium Channels; Calcium Signaling; Diabetic Cardiomyopathies; Humans; Mitochondria, Heart; Myocytes, Cardiac
PubMed: 33002576
DOI: 10.1016/j.bbadis.2020.165984 -
Biochimica Et Biophysica Acta.... May 2018Systemic changes during diabetes such as high glucose, dyslipidemia, hormonal changes and low grade inflammation, are believed to induce structural and functional... (Review)
Review
Systemic changes during diabetes such as high glucose, dyslipidemia, hormonal changes and low grade inflammation, are believed to induce structural and functional changes in the cardiomyocyte associated with the development of diabetic cardiomyopathy. One of the hallmarks of the diabetic heart is increased oxidative stress. NADPH-oxidases (NOXs) are important ROS-producing enzymes in the cardiomyocyte mediating both adaptive and maladaptive changes in the heart. NOXs have been suggested as a therapeutic target for several diabetic complications, but their role in diabetic cardiomyopathy is far from elucidated. In this review we aim to provide an overview of the current knowledge regarding the understanding of how NOXs influences cardiac adaptive and maladaptive processes in a "diabetic milieu". This article is part of a Special issue entitled Cardiac adaptations to obesity, diabetes and insulin resistance, edited by Professors Jan F.C. Glatz, Jason R.B. Dyck and Christine Des Rosiers.
Topics: Adaptation, Physiological; Animals; Blood Glucose; Calcium; Calcium Signaling; Diabetes Mellitus; Diabetic Cardiomyopathies; Energy Metabolism; Heart; Humans; Insulin Resistance; Lipids; Myocytes, Cardiac; NADPH Oxidases; Oxidative Stress; Reactive Oxygen Species
PubMed: 28754449
DOI: 10.1016/j.bbadis.2017.07.025