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Heart Failure Reviews Jan 2014Although heart disease due to diabetes is mainly associated with complications of the large vessels, microvascular abnormalities are also considered to be involved in... (Review)
Review
Although heart disease due to diabetes is mainly associated with complications of the large vessels, microvascular abnormalities are also considered to be involved in altering cardiac structure and function. Three major defects, such as endothelial dysfunction, alteration in the production/release of hormones, and shift in metabolism of smooth muscle cells, have been suggested to produce damage to the small arteries and capillaries (microangiopathy) due to hyperglycemia, and promote the development of diabetic cardiomyopathy. These factors may either act alone or in combination to produce oxidative stress as well as changes in cellular signaling and gene transcription, which in turn cause vasoconstriction and structural remodeling of the coronary vessels. Such alterations in microvasculature produce hypoperfusion of the myocardium and thereby lower the energy status resulting in changes in Ca(2+)-handling, apoptosis, and decreased cardiac contractile force. This article discusses diabetes-induced mechanisms of microvascular damage leading to cardiac dysfunction that is characterized by myocardial dilatation, cardiac hypertrophy as well as early diastolic and late systolic defects. Metabolic defects and changes in neurohumoral system due to diabetes, which promote disturbances in vascular homeostasis, are highlighted. In addition, increase in the vulnerability of the diabetic heart to the development of heart failure and the signaling pathways integrating nuclear factor κB and protein kinase C in diabetic cardiomyopathy are also described for comparison.
Topics: Diabetic Angiopathies; Diabetic Cardiomyopathies; Disease Progression; Endothelium, Vascular; Humans; Myocardium; Oxidative Stress; Vasodilation; Ventricular Remodeling
PubMed: 23456446
DOI: 10.1007/s10741-013-9378-7 -
The Journal of Pharmacy and Pharmacology Nov 2022Diabetic cardiomyopathy (DCM) is an end-point macrovascular complication associated with increased morbidity and mortality in 12% of diabetic patients. MicroRNAs... (Review)
Review
INTRODUCTION
Diabetic cardiomyopathy (DCM) is an end-point macrovascular complication associated with increased morbidity and mortality in 12% of diabetic patients. MicroRNAs (miRNAs) are small noncoding RNAs that can act as cardioprotective or cardiotoxic agents in DCM.
METHODS
We used PubMed as a search engine to collect and analyse data in published articles on the role of miRNAs on the pathophysiology, diagnosis and treatment of DCM.
RESULTS
MiRNAs play an essential role in the pathophysiology, diagnosis and treatment of DCM due to their distinct gene expression patterns in diabetic patients compared to healthy individuals. Advances in gene therapy have led to the discovery of potential circulating miRNAs, which can be used as biomarkers for DCM diagnosis and prognosis. Furthermore, targeted miRNA therapies in preclinical and clinical studies, such as using miRNA mimics and anti-miRNAs, have yielded promising results. Application of miRNA mimics and anti-miRNAs via different nanodrug delivery systems alleviate hypertrophy, fibrosis, oxidative stress and apoptosis of cardiomyocytes.
CONCLUSION
MiRNAs serve as attractive potential targets for DCM diagnosis, prognosis and treatment due to their distinctive expression profile in DCM development.
Topics: Humans; Biomarkers; Diabetes Mellitus; Diabetic Cardiomyopathies; Fibrosis; Genetic Therapy; MicroRNAs
PubMed: 36130185
DOI: 10.1093/jpp/rgac066 -
Clinical Science (London, England :... Aug 2023Diabetic cardiomyopathy (DCM) is a chronic metabolic disease with few effective therapeutic options. Immunoproteasome is an inducible proteasome that plays an important...
Diabetic cardiomyopathy (DCM) is a chronic metabolic disease with few effective therapeutic options. Immunoproteasome is an inducible proteasome that plays an important role in the regulation of many cardiovascular diseases, while its role in DCM remains under discussion. The present study aims to demonstrate whether inhibiting immunoproteasome subunit low molecular weight polypeptide 7 (LMP7) could alleviate DCM. Here, we established a type I diabetes mellitus mouse model by streptozotocin (STZ) in 8-week-old male wild-type C57BL/6J mice. We found that immunoproteasome subunit LMP7 was overexpressed in the heart of diabetic mice, while inhibiting LMP7 with pharmacological inhibitor ONX0914 significantly alleviated myocardial fibrosis and improved cardiac function. Besides, compared with diabetic mice, ONX0914 treatment reduced protein levels of mesenchymal markers (Vimentin, α-smooth muscle actin, and SM22α) and increased endothelial markers (VE-cadherin and CD31). In TGFβ1 stimulated HUVECs, we also observed that ONX0914 could inhibit endothelial-mesenchymal transition (EndMT). Mechanistically, we prove that ONX0914 could regulate autophagy activity both in vivo and vitro. Meanwhile, the protective effect of ONX0914 on TGFβ1 stimulated HUVECs could be abolished by 3-methyladenine (3MA) or hydroxychloroquine (CQ). All in all, our data highlight that inhibition of LMP7 with ONX0914 could ameliorate EndMT in diabetic mouse hearts at least in part via autophagy activation. Thus, LMP7 may be a potential therapeutic target for the DCM.
Topics: Animals; Male; Mice; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Mice, Inbred C57BL; Molecular Weight; Peptides
PubMed: 37551616
DOI: 10.1042/CS20230732 -
International Journal of Molecular... Dec 2016Diabetes mellitus is a chronic metabolic condition that affects carbohydrate, lipid and protein metabolism and may impair numerous organs and functions of the organism.... (Review)
Review
Diabetes mellitus is a chronic metabolic condition that affects carbohydrate, lipid and protein metabolism and may impair numerous organs and functions of the organism. Cardiac dysfunction afflicts many patients who experience the oxidative stress of the heart. Diabetic cardiomyopathy (DCM) is one of the major complications that accounts for more than half of diabetes-related morbidity and mortality cases. Chronic hyperglycemia and hyperlipidemia from diabetes mellitus cause cardiac oxidative stress, endothelial dysfunction, impaired cellular calcium handling, mitochondrial dysfunction, metabolic disturbances, and remodeling of the extracellular matrix, which ultimately lead to DCM. Although many studies have explored the mechanisms leading to DCM, the pathophysiology of DCM has not yet been fully clarified. In fact, as a potential mechanism, the associations between DCM development and mitogen-activated protein kinase (MAPK) activation have been the subjects of tremendous interest. Nonetheless, much remains to be investigated, such as tissue- and cell-specific processes of selection of MAPK activation between pro-apoptotic vs. pro-survival fate, as well as their relation with the pathogenesis of diabetes and associated complications. In general, it turns out that MAPK signaling pathways, such as extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal protein kinase (JNK) and p38 MAP kinase, are demonstrated to be actively involved in myocardial dysfunction, hypertrophy, fibrosis and heart failure. As one of MAPK family members, the activation of ERK1/2 has also been known to be involved in cardiac hypertrophy and dysfunction. However, many recent studies have demonstrated that ERK1/2 signaling activation also plays a crucial role in FGF21 signaling and exerts a protective environment of glucose and lipid metabolism, therefore preventing abnormal healing and cardiac dysfunction. The duration, extent, and subcellular compartment of ERK1/2 activation are vital to differential biological effects of ERK1/2. Moreover, many intracellular events, including mitochondrial signaling and protein kinases, manipulate signaling upstream and downstream of MAPK, to influence myocardial survival or death. In this review, we will summarize the roles of ERK1/2 pathways in DCM development by the evidence from current studies and will present novel opinions on "differential influence of ERK1/2 action in cardiac dysfunction, and protection against myocardial ischemia-reperfusion injury".
Topics: Animals; Diabetic Cardiomyopathies; Extracellular Signal-Regulated MAP Kinases; Histone Deacetylase Inhibitors; Humans; MAP Kinase Signaling System; MicroRNAs; Phosphorylation
PubMed: 27941647
DOI: 10.3390/ijms17122001 -
Biochimica Et Biophysica Acta May 2015Diabetic cardiomyopathy (DCM) is a common consequence of longstanding type 2 diabetes mellitus (T2DM) and encompasses structural, morphological, functional, and... (Review)
Review
Diabetic cardiomyopathy (DCM) is a common consequence of longstanding type 2 diabetes mellitus (T2DM) and encompasses structural, morphological, functional, and metabolic abnormalities in the heart. Myocardial energy metabolism depends on mitochondria, which must generate sufficient ATP to meet the high energy demands of the myocardium. Dysfunctional mitochondria are involved in the pathophysiology of diabetic heart disease. A large body of evidence implicates myocardial insulin resistance in the pathogenesis of DCM. Recent studies show that insulin signaling influences myocardial energy metabolism by impacting cardiomyocyte mitochondrial dynamics and function under physiological conditions. However, comprehensive understanding of molecular mechanisms linking insulin signaling and changes in the architecture of the mitochondrial network in diabetic cardiomyopathy is lacking. This review summarizes our current understanding of how defective insulin signaling impacts cardiac function in diabetic cardiomyopathy and discusses the potential role of mitochondrial dynamics.
Topics: Animals; Diabetic Cardiomyopathies; Humans; Insulin; Mitochondrial Dynamics; Models, Biological; Myocardium; Signal Transduction
PubMed: 25686534
DOI: 10.1016/j.bbamcr.2015.02.005 -
Biomedicine & Pharmacotherapy =... Oct 2018
Review
Topics: Diabetic Cardiomyopathies; Humans; Insulin Resistance; MicroRNAs; Molecular Targeted Therapy; Oxidative Stress; Renin-Angiotensin System
PubMed: 30119169
DOI: 10.1016/j.biopha.2018.07.051 -
Frontiers in Immunology 2022The diabetic population has been increasing in the past decades and diabetic cardiomyopathy (DCM), a pathology that is defined by the presence of cardiac remodeling and... (Review)
Review
The diabetic population has been increasing in the past decades and diabetic cardiomyopathy (DCM), a pathology that is defined by the presence of cardiac remodeling and dysfunction without conventional cardiac risk factors such as hypertension and coronary heart diseases, would eventually lead to fatal heart failure in the absence of effective treatment. Impaired insulin signaling, commonly known as insulin resistance, plays an important role in the development of DCM. A family of integral membrane proteins named caveolins (mainly caveolin-1 and caveolin-3 in the myocardium) and a protein hormone adiponectin (APN) have all been shown to be important for maintaining normal insulin signaling. Abnormalities in caveolins and APN have respectively been demonstrated to cause DCM. This review aims to summarize recent research findings of the roles and mechanisms of caveolins and APN in the development of DCM, and also explore the possible interplay between caveolins and APN.
Topics: Humans; Diabetic Cardiomyopathies; Caveolin 1; Myocardium; Insulin Resistance; Insulin; Adiponectin; Diabetes Mellitus
PubMed: 36405687
DOI: 10.3389/fimmu.2022.951381 -
Heart Failure Clinics Oct 2012The study of diabetic cardiomyopathy is an area of significant interest given the strong association between diabetes and the risk of heart failure. Many unanswered... (Review)
Review
The study of diabetic cardiomyopathy is an area of significant interest given the strong association between diabetes and the risk of heart failure. Many unanswered questions remain regarding the clinical definition and pathogenesis of this metabolic cardiomyopathy. This article reviews the current understanding of diabetic cardiomyopathy with a particular emphasis on the unresolved issues that have limited translation of scientific discovery to patient bedside.
Topics: Diabetes Mellitus; Diabetic Cardiomyopathies; Disease Progression; Fatty Acids, Nonesterified; Humans; Inflammation; Lipid Metabolism; Male; Middle Aged; Mitochondria; Myocardial Infarction; Myocardium; Oxidative Stress; Prognosis; Risk Factors
PubMed: 22999244
DOI: 10.1016/j.hfc.2012.06.007 -
Prostaglandins & Other Lipid Mediators Oct 2020The global epidemic of cardiovascular disease continues unabated and remains the leading cause of death both in the US and worldwide. We hereby summarize the available... (Review)
Review
The global epidemic of cardiovascular disease continues unabated and remains the leading cause of death both in the US and worldwide. We hereby summarize the available therapies for diabetes and cardiovascular disease in diabetics. Clearly, the current approaches to diabetic heart disease often target the manifestations and certain mediators but not the specific pathways leading to myocardial injury, remodeling and dysfunction. Better understanding of the molecular events determining the evolution of diabetic cardiomyopathy will provide insight into the development of specific and targeted therapies. Recent studies largely increased our understanding of the role of enhanced inflammatory response, ROS production, as well as the contribution of Cyp-P450-epoxygenase-derived epoxyeicosatrienoic acid (EET), Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1α (PGC-1α), Heme Oxygenase (HO)-1 and 20-HETE in pathophysiology and therapy of cardiovascular disease. PGC-1α increases production of the HO-1 which has a major role in protecting the heart against oxidative stress, microcirculation and mitochondrial dysfunction. This review describes the potential drugs and their downstream targets, PGC-1α and HO-1, as major loci for developing therapeutic approaches beside diet and lifestyle modification for the treatment and prevention of heart disease associated with obesity and diabetes.
Topics: Animals; Antioxidants; Diabetes Mellitus; Diabetic Cardiomyopathies; Humans; Oxidative Stress
PubMed: 32413571
DOI: 10.1016/j.prostaglandins.2020.106454 -
Current Pharmaceutical Design Oct 2011Diabetic cardiopathy includes a specific cardiomyopathy, which occurs in the absence of coronary heart disease under diabetes mellitus. Hallmarks of diabetic... (Review)
Review
Diabetic cardiopathy includes a specific cardiomyopathy, which occurs in the absence of coronary heart disease under diabetes mellitus. Hallmarks of diabetic cardiomyopathy are besides others, interstitial inflammation, cardiac oxidative stress, interstitial and perivascular fibrosis, cardiac apoptosis, intramyocardial microangiopathy, endothelial dysfunction, abnormal intracellular Ca²⁺-handling, cardiomyocyte hypertrophy, and impaired cardiac stem cells. Since mesenchymal stromal cells have been shown to have anti-diabetic as well as cardioprotective features, we summarize in this review how they can indirectly affect diabetic cardiomyopathy via their influence on the metabolic trigger hyperglycemia, and how they can directly influence the cardiac cellular consequences typical for diabetic cardiomyopathy via their immunomodulatory, anti-oxidative, anti-fibrotic, anti-apoptotic, pro-angiogenic, and endothelial-protective features, and their ability to activate cardiac progenitor cells. Furthermore, the dysfunctionality of (bone marrow-derived) mesenchymal stromal cells under diabetes mellitus and potential strategies to overcome this impairment in cell functionality are outlined.
Topics: Animals; Apoptosis; Calcium; Cell Differentiation; Cell Lineage; Diabetic Cardiomyopathies; Humans; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Neovascularization, Physiologic
PubMed: 21919875
DOI: 10.2174/138161211797904163