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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 -
The Journal of Physiology Jul 2020The prevalence of obesity, insulin resistance and diabetes is increasing rapidly. Most patients with these disorders have hypertriglyceridaemia and increased plasma... (Review)
Review
The prevalence of obesity, insulin resistance and diabetes is increasing rapidly. Most patients with these disorders have hypertriglyceridaemia and increased plasma levels of fatty acids, which are taken up and stored in lipid droplets in the heart. Intramyocardial lipids that exceed the capacity for storage and oxidation can be lipotoxic and induce non-ischaemic and non-hypertensive cardiomyopathy, termed diabetic or lipotoxic cardiomyopathy. The clinical features of diabetic cardiomyopathy are cardiac hypertrophy and diastolic dysfunction, which lead to heart failure, especially heart failure with preserved ejection fraction. Although the pathogenesis of the cardiomyopathy is multifactorial, diabetic dyslipidaemia and intramyocardial lipid accumulation are the key pathological features, triggering cellular signalling and modifications of proteins and lipids via generation of toxic metabolic intermediates. Most clinical studies have shown no beneficial effect of anti-diabetic agents and statins on outcomes in heart failure patients without atherosclerotic diseases, indicating the importance of identifying underlying mechanisms and early interventions for diabetic cardiomyopathy. Here, we summarize the molecular mechanisms of diabetic cardiomyopathy, with a special emphasis on cardiac lipotoxicity, and discuss the role of peroxisome proliferator-activated receptor α and dysregulated fatty acid metabolism as potential therapeutic targets.
Topics: Diabetes Mellitus; Diabetic Cardiomyopathies; Humans; Hypoglycemic Agents; Insulin Resistance; Lipid Metabolism; Myocardium; Obesity
PubMed: 30869158
DOI: 10.1113/JP276747 -
Frontiers in Endocrinology 2022The cardiovascular complications contribute to a majority of diabetes associated morbidity and mortality, accounting for 44% of death in those patients with type 1... (Review)
Review
The cardiovascular complications contribute to a majority of diabetes associated morbidity and mortality, accounting for 44% of death in those patients with type 1 diabetes mellitus (DM) and 52% of deaths in type 2 DM. Diabetes elicits cardiovascular dysfunction through 2 major mechanisms: ischemic and non-ischemic. Non-ischemic injury is usually under-recognized although common in DM patients, and also a pathogenic factor of heart failure in those diabetic individuals complicated with ischemic heart disease. Diabetic cardiomyopathy (DCM) is defined as a heart disease in which the myocardium is structurally and functionally abnormal in the absence of coronary artery disease, hypertensive, valvular, or congenital heart disorders in diabetic patients, theoretically caused by non-ischemic injury solely. Current therapeutic strategies targeting DCM mainly address the increased blood glucose levels, however, the effects on heart function are disappointed. Accumulating data indicate endothelial dysfunction plays a critical role in the initiation and development of DCM. Hyperglycemia, hyperinsulinemia, and insulin resistance cause the damages of endothelial function, including barrier dysfunction, impaired nitric oxide (NO) activity, excessive reactive oxygen species (ROS) production, oxidative stress, and inflammatory dysregulation. In turn, endothelial dysfunction promotes impaired myocardial metabolism, intracellular Ca mishandling, endoplasmic reticulum (ER) stress, mitochondrial defect, accumulation of advanced glycation end products, and extracellular matrix (ECM) deposit, leads to cardiac stiffness, fibrosis, and remodeling, eventually results in cardiac diastolic dysfunction, systolic dysfunction, and heart failure. While endothelial dysfunction is closely related to cardiac dysfunction and heart failure seen in DCM, clinical strategies for restoring endothelial function are still missing. This review summarizes the timely findings related to the effects of endothelial dysfunction on the disorder of myocardium as well as cardiac function, provides mechanical insights in pathogenesis and pathophysiology of DCM developing, and highlights potential therapeutic targets.
Topics: Diabetes Mellitus; Diabetic Cardiomyopathies; Heart Failure; Humans; Hyperglycemia; Myocardium; Oxidative Stress
PubMed: 35464057
DOI: 10.3389/fendo.2022.851941 -
Advanced Science (Weinheim,... Nov 2022Diabetes manifests as chronic inflammation and leads to the development diabetic cardiomyopathy (DCM). Targeting key proteins in inflammatory signaling may provide new...
Diabetes manifests as chronic inflammation and leads to the development diabetic cardiomyopathy (DCM). Targeting key proteins in inflammatory signaling may provide new therapy for DCM. In this study, the authors explore the pharmacological effects and mechanisms of Schisandrin B (Sch B), a natural compound with anti-inflammatory activity against DCM. It is shown that Sch B prevents high-level glucose (HG)-induced hypertrophic and fibrotic responses in cultured cardiomyocytes. RNA sequencing and inflammatory qPCR microarray show that Sch B mainly affects myeloid differentiation primary response 88 (MyD88)-dependent inflammatory gene expression in HG-challenged cardiomyocytes. Further studies indicate that Sch B directly binds to and inhibits MyD88 activation, but does not alter MyD88-independent Toll-like receptor signaling in vivo and in vitro. Inhibiting or silencing MyD88 is associated with reduced levels of HG-induced inflammatory cytokines and myocardial injuries in vitro. Treatment of type 1 and type 2 diabetic mice with Sch B protects heart function, reduces myocardial injuries, and decreases secretion of inflammatory cytokines. Cardiomyocyte-specific MyD88 knockout also protects mice against cardiac inflammation and injury in type 1 diabetic mice. In conclusion, these studies show that cardiomyocyte MyD88 plays an apathogenetic role in DCM and Sch B specifically targets MyD88 to reduce inflammatory DCM.
Topics: Animals; Mice; Cytokines; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Inflammation; Myeloid Differentiation Factor 88
PubMed: 36180407
DOI: 10.1002/advs.202202590 -
Cardiovascular Diabetology Feb 2019Hyperglycaemia associated with myocardial oxidative stress and fibrosis is the main cause of diabetic cardiomyopathy. Empagliflozin, a sodium-glucose cotransporter 2...
BACKGROUND
Hyperglycaemia associated with myocardial oxidative stress and fibrosis is the main cause of diabetic cardiomyopathy. Empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor has recently been reported to improve glycaemic control in patients with type 2 diabetes in an insulin-independent manner. The aim of this study was to investigate the effect of empagliflozin on myocardium injury and the potential mechanism in type 2 diabetic KK-Ay mice.
METHODS
Thirty diabetic KK-Ay mice were administered empagliflozin (10 mg/kg/day) by oral gavage daily for 8 weeks. After 8 weeks, heart structure and function were evaluated by echocardiography. Oxidants and antioxidants were measured and cardiac fibrosis was analysed using immunohistochemistry, Masson's trichrome stain and Western blot.
RESULTS
Results showed that empagliflozin improved diabetic myocardial structure and function, decreased myocardial oxidative stress and ameliorated myocardial fibrosis. Further study indicated that empagliflozin suppressed oxidative stress and fibrosis through inhibition of the transforming growth factor β/Smad pathway and activation of Nrf2/ARE signaling.
CONCLUSIONS
Glycaemic control with empagliflozin significantly ameliorated myocardial oxidative stress injury and cardiac fibrosis in diabetic mice. Taken together, these results indicate that the empagliflozin is a promising agent for the prevention and treatment of diabetic cardiomyopathy.
Topics: Animals; Antioxidant Response Elements; Antioxidants; Benzhydryl Compounds; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Disease Models, Animal; Fibrosis; Glucosides; Mice, Inbred C57BL; Myocardium; NF-E2-Related Factor 2; Oxidative Stress; Phosphorylation; Signal Transduction; Smad Proteins; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Transforming Growth Factor beta1; Ventricular Function, Left; Ventricular Remodeling
PubMed: 30710997
DOI: 10.1186/s12933-019-0816-2 -
Circulation Research Apr 2019Diabetic patients develop cardiomyopathy characterized by hypertrophy, diastolic dysfunction, and intracellular lipid accumulation, termed lipotoxicity. Diabetic hearts...
RATIONALE
Diabetic patients develop cardiomyopathy characterized by hypertrophy, diastolic dysfunction, and intracellular lipid accumulation, termed lipotoxicity. Diabetic hearts utilize fatty acids as a major energy source, which produces high levels of oxidative stress, thereby inducing mitochondrial dysfunction.
OBJECTIVE
To elucidate how mitochondrial function is regulated in diabetic cardiomyopathy.
METHODS AND RESULTS
Mice were fed either a normal diet or high-fat diet (HFD, 60 kcal % fat). Although autophagic flux was activated by HFD consumption, peaking at 6 weeks ( P<0.05), it was attenuated thereafter. Mitophagy, evaluated with Mito-Keima, was increased after 3 weeks of HFD feeding (mitophagy area: 8.3% per cell with normal diet and 12.4% with HFD) and continued to increase even after 2 months ( P<0.05). By isolating adult cardiomyocytes from GFP-LC3 mice fed HFD, we confirmed that mitochondria were sequestrated by LC3-positive autophagosomes during mitophagy. In wild-type mice, cardiac hypertrophy, diastolic dysfunction (end diastolic pressure-volume relationship =0.051±0.009 in normal diet and 0.11±0.004 in HFD) and lipid accumulation occurred within 2 months of HFD feeding ( P<0.05). Deletion of atg7 impaired mitophagy, increased lipid accumulation, exacerbated diastolic dysfunction (end diastolic pressure-volume relationship =0.11±0.004 in wild type and 0.152±0.019 in atg7 cKO; P<0.05) and induced systolic dysfunction (end systolic pressure-volume relationship =24.86±2.46 in wild type and 15.93±1.76 in atg7 cKO; P<0.05) during HFD feeding. Deletion of Parkin partially inhibited mitophagy, increased lipid accumulation and exacerbated diastolic dysfunction (end diastolic pressure-volume relationship =0.124±0.005 in wild type and 0.176±0.018 in Parkin KO, P<0.05) in response to HFD feeding. Injection of TB1 (Tat-Beclin1) activated mitophagy, attenuated mitochondrial dysfunction, decreased lipid accumulation, and protected against cardiac diastolic dysfunction (end diastolic pressure-volume relationship =0.110±0.009 in Control peptide and 0.078±0.015 in TB1, P<0.05) during HFD feeding.
CONCLUSIONS
Mitophagy serves as an essential quality control mechanism for mitochondria in the heart during HFD consumption. Impairment of mitophagy induces mitochondrial dysfunction and lipid accumulation, thereby exacerbating diabetic cardiomyopathy. Conversely, activation of mitophagy protects against HFD-induced diabetic cardiomyopathy.
Topics: Animals; Autophagy-Related Protein 7; Cardiomegaly; Diabetic Cardiomyopathies; Diet, High-Fat; Female; Heart; Humans; Male; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Mitophagy; Myocytes, Cardiac
PubMed: 30786833
DOI: 10.1161/CIRCRESAHA.118.314607 -
ELife Apr 2023Myocardial fibrosis is the characteristic pathology of diabetes-induced cardiomyopathy. Therefore, an in-depth study of cardiac heterogeneity and cell-to-cell...
Myocardial fibrosis is the characteristic pathology of diabetes-induced cardiomyopathy. Therefore, an in-depth study of cardiac heterogeneity and cell-to-cell interactions can help elucidate the pathogenesis of diabetic myocardial fibrosis and identify treatment targets for the treatment of this disease. In this study, we investigated intercellular communication drivers of myocardial fibrosis in mouse heart with high-fat-diet/streptozotocin-induced diabetes at single-cell resolution. Intercellular and protein-protein interaction networks of fibroblasts and macrophages, endothelial cells, as well as fibroblasts and epicardial cells revealed critical changes in ligand-receptor interactions such as Pdgf(s)-Pdgfra and Efemp1-Egfr, which promote the development of a profibrotic microenvironment during the progression of and confirmed that the specific inhibition of the Pdgfra axis could significantly improve diabetic myocardial fibrosis. We also identified phenotypically distinct and fibroblast subpopulations associated with pathological extracellular matrix remodeling, of which the fibroblasts were found to be the most profibrogenic under diabetic conditions. Finally, we validated the role of the hub gene-mediated intercellular communication drivers of diabetic myocardial fibrosis in fibroblasts, and confirmed the results through AAV9-mediated knockdown in the heart of diabetic mice. In summary, cardiac cell mapping provides novel insights into intercellular communication drivers involved in pathological extracellular matrix remodeling during diabetic myocardial fibrosis.
Topics: Mice; Animals; Diabetic Cardiomyopathies; Myocardium; Diabetes Mellitus, Experimental; Endothelial Cells; Single-Cell Gene Expression Analysis; Cell Communication; Fibrosis; Fibroblasts
PubMed: 37010266
DOI: 10.7554/eLife.80479 -
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 -
Cardiovascular Diabetology Jan 2020Diabetes mellitus type 2 (DM2) is a risk factor for developing heart failure but there is no specific therapy for diabetic heart disease. Sodium glucose transporter 2...
BACKGROUND
Diabetes mellitus type 2 (DM2) is a risk factor for developing heart failure but there is no specific therapy for diabetic heart disease. Sodium glucose transporter 2 inhibitors (SGLT2I) are recently developed diabetic drugs that primarily work on the kidney. Clinical data describing the cardiovascular benefits of SGLT2Is highlight the potential therapeutic benefit of these drugs in the prevention of cardiovascular events and heart failure. However, the underlying mechanism of protection remains unclear. We investigated the effect of Dapagliflozin-SGLT2I, on diabetic cardiomyopathy in a mouse model of DM2.
METHODS
Cardiomyopathy was induced in diabetic mice (db/db) by subcutaneous infusion of angiotensin II (ATII) for 30 days using an osmotic pump. Dapagliflozin (1.5 mg/kg/day) was administered concomitantly in drinking water. Male homozygous, 12-14 weeks old WT or db/db mice (n = 4-8/group), were used for the experiments. Isolated cardiomyocytes were exposed to glucose (17.5-33 mM) and treated with Dapagliflozin in vitro. Intracellular calcium transients were measured using a fluorescent indicator indo-1.
RESULTS
Angiotensin II infusion induced cardiomyopathy in db/db mice, manifested by cardiac hypertrophy, myocardial fibrosis and inflammation (TNFα, TLR4). Dapagliflozin decreased blood glucose (874 ± 111 to 556 ± 57 mg/dl, p < 0.05). In addition it attenuated fibrosis and inflammation and increased the left ventricular fractional shortening in ATII treated db/db mice. In isolated cardiomyocytes Dapagliflozin decreased intracellular calcium transients, inflammation and ROS production. Finally, voltage-dependent L-type calcium channel (CACNA1C), the sodium-calcium exchanger (NCX) and the sodium-hydrogen exchanger 1 (NHE) membrane transporters expression was reduced following Dapagliflozin treatment.
CONCLUSION
Dapagliflozin was cardioprotective in ATII-stressed diabetic mice. It reduced oxygen radicals, as well the activity of membrane channels related to calcium transport. The cardioprotective effect manifested by decreased fibrosis, reduced inflammation and improved systolic function. The clinical implication of our results suggest a novel pharmacologic approach for the treatment of diabetic cardiomyopathy through modulation of ion homeostasis.
Topics: Angiotensin II; Animals; Benzhydryl Compounds; Biomarkers; Blood Glucose; Calcium Channels, L-Type; Calcium Signaling; Cells, Cultured; Diabetes Mellitus; Diabetic Cardiomyopathies; Disease Models, Animal; Fibrosis; Glucosides; Inflammation Mediators; Male; Mice, Inbred C57BL; Myocytes, Cardiac; Rats, Sprague-Dawley; Sodium-Calcium Exchanger; Sodium-Glucose Transporter 2 Inhibitors; Sodium-Hydrogen Exchanger 1; Ventricular Function, Left
PubMed: 31924211
DOI: 10.1186/s12933-019-0980-4 -
Cardiovascular Diabetology Jan 2021The prevalence of cardiomyopathy is higher in diabetic patients than those without diabetes. Diabetic cardiomyopathy (DCM) is defined as a clinical condition of abnormal... (Review)
Review
The prevalence of cardiomyopathy is higher in diabetic patients than those without diabetes. Diabetic cardiomyopathy (DCM) is defined as a clinical condition of abnormal myocardial structure and performance in diabetic patients without other cardiac risk factors, such as coronary artery disease, hypertension, and significant valvular disease. Multiple molecular events contribute to the development of DCM, which include the alterations in energy metabolism (fatty acid, glucose, ketone and branched chain amino acids) and the abnormalities of subcellular components in the heart, such as impaired insulin signaling, increased oxidative stress, calcium mishandling and inflammation. There are no specific drugs in treating DCM despite of decades of basic and clinical investigations. This is, in part, due to the lack of our understanding as to how heart failure initiates and develops, especially in diabetic patients without an underlying ischemic cause. Some of the traditional anti-diabetic or lipid-lowering agents aimed at shifting the balance of cardiac metabolism from utilizing fat to glucose have been shown inadequately targeting multiple aspects of the conditions. Peroxisome proliferator-activated receptor α (PPARα), a transcription factor, plays an important role in mediating DCM-related molecular events. Pharmacological targeting of PPARα activation has been demonstrated to be one of the important strategies for patients with diabetes, metabolic syndrome, and atherosclerotic cardiovascular diseases. The aim of this review is to provide a contemporary view of PPARα in association with the underlying pathophysiological changes in DCM. We discuss the PPARα-related drugs in clinical applications and facts related to the drugs that may be considered as risky (such as fenofibrate, bezafibrate, clofibrate) or safe (pemafibrate, metformin and glucagon-like peptide 1-receptor agonists) or having the potential (sodium-glucose co-transporter 2 inhibitor) in treating DCM.
Topics: Animals; Diabetic Cardiomyopathies; Energy Metabolism; Glucagon-Like Peptide-1 Receptor; Heart Failure; Humans; Incretins; Myocytes, Cardiac; PPAR alpha; Signal Transduction; Sodium-Glucose Transporter 2 Inhibitors; Ventricular Dysfunction, Left; Ventricular Function, Left; Ventricular Remodeling
PubMed: 33397369
DOI: 10.1186/s12933-020-01188-0