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Cardiovascular Diabetology Apr 2023Among the complications of diabetes, cardiovascular events and cardiac insufficiency are considered two of the most important causes of death. Experimental and clinical... (Review)
Review
Among the complications of diabetes, cardiovascular events and cardiac insufficiency are considered two of the most important causes of death. Experimental and clinical evidence supports the effectiveness of SGLT2i for improving cardiac dysfunction. SGLT2i treatment benefits metabolism, microcirculation, mitochondrial function, fibrosis, oxidative stress, endoplasmic reticulum stress, programmed cell death, autophagy, and the intestinal flora, which are involved in diabetic cardiomyopathy. This review summarizes the current knowledge of the mechanisms of SGLT2i for the treatment of diabetic cardiomyopathy.
Topics: Humans; Sodium-Glucose Transporter 2 Inhibitors; Diabetic Cardiomyopathies; Heart Failure; Diabetes Mellitus, Type 2
PubMed: 37055837
DOI: 10.1186/s12933-023-01816-5 -
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 -
Cardiovascular Diabetology Oct 2022Diabetic cardiomyopathy is characterized by left ventricle dysfunction, cardiomyocyte apoptosis, and interstitial fibrosis and is a serious complication of diabetes...
BACKGROUND
Diabetic cardiomyopathy is characterized by left ventricle dysfunction, cardiomyocyte apoptosis, and interstitial fibrosis and is a serious complication of diabetes mellitus (DM). Autophagy is a mechanism that is essential for maintaining normal heart morphology and function, and its dysregulation can produce pathological effects on diabetic hearts. Neuregulin-4 (Nrg4) is an adipokine that exerts protective effects against metabolic disorders and insulin resistance. The aim of this study was to explore whether Nrg4 could ameliorate DM-induced myocardial injury by regulating autophagy.
METHODS
Four weeks after the establishment of a model of type 1 diabetes in mice, the mice received Nrg4 treatment (with or without an autophagy inhibitor) for another 4 weeks. The cardiac functions, histological structures and cardiomyocyte apoptosis were investigated. Autophagy-related protein levels along with related signalling pathways that regulate autophagy were evaluated. In addition, the effects of Nrg4 on autophagy were also determined in cultured primary cardiomyocytes.
RESULTS
Nrg4 alleviated myocardial injury both in vivo and in vitro. The autophagy level was decreased in type 1 diabetic mice, and Nrg4 intervention reactivated autophagy. Furthermore, Nrg4 intervention was found to activate autophagy via the AMPK/mTOR signalling pathway. Moreover, when autophagy was suppressed or the AMPK/mTOR pathway was inhibited, the beneficial effects of Nrg4 were diminished.
CONCLUSION
Nrg4 intervention attenuated diabetic cardiomyopathy by promoting autophagy in type 1 diabetic mice. Additionally, Nrg4 induced autophagy via the AMPK/mTOR signalling pathway.
Topics: AMP-Activated Protein Kinases; Adipokines; Animals; Apoptosis; Autophagy; Autophagy-Related Proteins; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Cardiomyopathies; Mice; Neuregulins; TOR Serine-Threonine Kinases
PubMed: 36221104
DOI: 10.1186/s12933-022-01643-0 -
Oxidative Medicine and Cellular... 2022Diabetes mellitus (DM) can induce cardiomyocyte injury and lead to diabetic cardiomyopathy (DCM) which presently has no specific treatments and consequently increase...
BACKGROUND
Diabetes mellitus (DM) can induce cardiomyocyte injury and lead to diabetic cardiomyopathy (DCM) which presently has no specific treatments and consequently increase risk of mortality.
OBJECTIVE
To characterize the therapeutic effect of 6-gingerol (6-G) on DCM and identify its potential mechanism.
METHODS
In vivo streptozotocin- (STZ-) induced DM model was established by using a high-fat diet and STZ, followed by low-dose (25 mg/kg) and high-dose (75 mg/kg) 6-G intervention. For an in vitro DCM model, H9c2 rat cardiomyoblast cells were stimulated with high glucose (glucose = 33 mM) and palmitic acid (100 M) and then treated with 6-G (100 M). Histological and echocardiographic analyses were used to assess the effect of 6-G on cardiac structure and function in DCM. Western blotting, ELISA, and real-time qPCR were used to assess the expression of ferroptosis, inflammation, and the Nrf2/HO-1 pathway-related proteins and RNAs. Protein expression of collagen I and collagen III was assessed by immunohistochemistry, and kits were used to assay SOD, MDA, and iron levels.
RESULTS
The results showed that 6-G decreased cardiac injury in both mouse and cell models of DCM. The cardiomyocyte hypertrophy and interstitial fibrosis were attenuated by 6-G treatment in vivo and resulted in an improved heart function. 6-G inhibited the expression of ferroptosis-related protein FACL4 and the content of iron and enhanced the expression of anti-ferroptosis-related protein GPX4. In addition, 6-G also diminished the secretion of inflammatory cytokines, including IL-1, IL-6, and TNF-. 6-G treatment activated the Nrf2/HO-1 pathway, enhanced antioxidative stress capacity proved by increased activity of SOD, and decreased MDA production. Compared with in vivo, 6-G treatment of H9c2 cells treated with high glucose and palmitic acid could produce a similar effect.
CONCLUSION
These findings suggest that 6-G could protect against DCM by the mechanism of ferroptosis inhibition and inflammation reduction via enhancing the Nrf2/HO-1 pathway.
Topics: Rats; Mice; Animals; Diabetic Cardiomyopathies; NF-E2-Related Factor 2; Palmitic Acid; Oxidative Stress; Inflammation; Glucose; Superoxide Dismutase; Diabetes Mellitus
PubMed: 36624878
DOI: 10.1155/2022/3027514 -
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 -
Redox Biology Oct 2021Diabetes disrupts mitochondrial function and often results in diabetic cardiomyopathy (DCM). Paeonol is a bioactive compound that has been reported to have...
Diabetes disrupts mitochondrial function and often results in diabetic cardiomyopathy (DCM). Paeonol is a bioactive compound that has been reported to have pharmacological potential for cardiac and mitochondrial protection. This study aims to explore the effects of paeonol on mitochondrial disorderes in DCM and the underlying mechanisms. We showed that paeonol promoted Opa1-mediated mitochondrial fusion, inhibited mitochondrial oxidative stress, and preserved mitochondrial respiratory capacity and cardiac performance in DCM in vivo and in vitro. Knockdown of Opa1 blunted the above protective effects of paeonol in both diabetic hearts and high glucose-treated cardiomyocytes. Mechanistically, inhibitor screening, siRNA knockdown and chromatin immunoprecipitation experiments showed that paeonol-promoted Opa1-mediated mitochondrial fusion required the activation of Stat3, which directly bound to the promoter of Opa1 to upregulate its transcriptional expression. Moreover, pharmmapper screening and molecular docking studies revealed that CK2α served as a direct target of paeonol that interacted with Jak2 and induced the phosphorylation and activation of Jak2-Stat3. Knockdown of CK2α blunted the promoting effect of paeonol on Jak2-Stat3 phosphorylation and Opa1-mediated mitochondrial fusion. Collectively, we have demonstrated for the first time that paeonol is a novel mitochondrial fusion promoter in protecting against hyperglycemia-induced mitochondrial oxidative injury and DCM at least partially via an Opa1-mediated mechanism, a process in which paeonol interacts with CK2α and restores its kinase activity that subsequently increasing Jak2-Stat3 phosphorylation and enhancing the transcriptional level of Opa1. These findings suggest that paeonol or the promotion of mitochondrial fusion might be a promising strategy for the treatment of DCM.
Topics: Acetophenones; Diabetes Mellitus; Diabetic Cardiomyopathies; GTP Phosphohydrolases; Humans; Mitochondrial Dynamics; Molecular Docking Simulation; STAT3 Transcription Factor
PubMed: 34418601
DOI: 10.1016/j.redox.2021.102098 -
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 -
Cardiovascular Diabetology Jul 2022Diabetes is a metabolic disorder that affects millions of people worldwide. Diabetic heart disease (DHD) comprises coronary artery disease, heart failure, cardiac... (Review)
Review
Diabetes is a metabolic disorder that affects millions of people worldwide. Diabetic heart disease (DHD) comprises coronary artery disease, heart failure, cardiac autonomic neuropathy, peripheral arterial disease, and diabetic cardiomyopathy. The onset and progression of DHD have been attributed to molecular alterations in response to hyperglycemia in diabetes. In this context, microRNAs (miRNAs) have been demonstrated to have a significant role in the development and progression of DHD. In addition to their effects on the host cells, miRNAs can be released into circulation after encapsulation within the exosomes. Exosomes are extracellular nanovesicles ranging from 30 to 180 nm in diameter secreted by all cell types. They carry diverse cargos that are altered in response to various conditions in their parent cells. Exosomal miRNAs have been extensively studied in recent years due to their role and therapeutic potential in DHD. This review will first provide an overview of exosomes, their biogenesis and function, followed by the role of exosomes in cardiovascular disease and then focuses on the known role of exosomes and associated miRNAs in DHD.
Topics: Cardiovascular Diseases; Diabetes Mellitus; Diabetic Cardiomyopathies; Exosomes; Humans; MicroRNAs
PubMed: 35778763
DOI: 10.1186/s12933-022-01544-2 -
Redox Biology Feb 2024Ketone bodies are considered as an alternative energy source for diabetic cardiomyopathy (DCM) and can improve the energy supply of the heart muscle, suggesting that it...
Ketone bodies are considered as an alternative energy source for diabetic cardiomyopathy (DCM) and can improve the energy supply of the heart muscle, suggesting that it may be an important area of research and development as a therapeutic target for DCM. Cumulative cardiovascular trials have shown that sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce cardiovascular events in diabetic populations. Whether SGLT2 inhibitors improve DCM by enhancing ketone body metabolism remains and whether they help prevent oxidative damage remains to be clarified. Here, we present the combined results of nine GSE datasets for diabetic cardiomyopathy (GSE215979, GSE161931, GSE145294, GSE161052, GSE173384, GSE123975, GSE161827, GSE210612, and GSE5606). We found significant up-regulated gene 3-hydroxymethylglutaryl CoA synthetase 2 (HMGCS2) and down-regulated gene 3-hydroxybutyrate dehydrogenase (BDH1) and 3-oxoacid CoA-transferase1 (OXCT1), respectively. Based on the analysis of the constructed protein interaction network, it was found that HMGCS2 was in the core position of the interaction network. In addition, Gene ontology (GO) enrichment analysis mainly focused on redox process, acyl-CoA metabolic process, catalytic activity, redox enzyme activity and mitochondria. The activity of HMGCS2 in DCM heart was increased, while the expression of ketolysis enzymes BDH1 and OXCT1 was inhibited. In vivo, Empagliflozin (Emp) treated DCM group significantly decreased ventricular weight, myocardial cell cross-sectional area, and myocardial fibrosis. In addition, Emp further promoted the activity of BDH1 and OXCT1, increased the utilization of ketone bodies, further promoted the activity of HMGCS2 in DCM, and increased the synthesis of ketone bodies, prevented mitochondrial breakage and dysfunction, increased myocardial ATP to provide sufficient energy, inhibited oxidative stress and apoptosis of cardiac cells ex vivo, and improved the myocardial dysfunction of DCM. Emp can improve mitochondrial dysfunction in diabetic cardiomyopathy by regulating ketone body metabolism and oxidative stress. These findings provide a theoretical basis for evaluating Emp as a treatment for DCM.
Topics: Humans; Diabetic Cardiomyopathies; Oxidative Stress; Myocytes, Cardiac; Ketone Bodies; Mitochondrial Diseases; Diabetes Mellitus; Benzhydryl Compounds; Glucosides
PubMed: 38160540
DOI: 10.1016/j.redox.2023.103010 -
Sheng Li Xue Bao : [Acta Physiologica... Jun 2022Histone methylation is one of the key post-translational modifications that plays a critical role in various heart diseases, including diabetic cardiomyopathy. A great... (Review)
Review
Histone methylation is one of the key post-translational modifications that plays a critical role in various heart diseases, including diabetic cardiomyopathy. A great deal of evidence has shown that histone methylation is closely related to hyperglycemia, insulin resistance, lipid and advanced glycation end products deposition, inflammatory and oxidative stress, endoplasmic reticulum stress and cell apoptosis, and these pathological factors play an important role in the pathogenesis of diabetic cardiomyopathy. In order to provide a novel theoretical basis and potential targets for the treatment of diabetic cardiomyopathy from the perspective of epigenetics, this review discussed and elucidated the association between histone methylation and the pathogenesis of diabetic cardiomyopathy in details.
Topics: Diabetes Mellitus; Diabetic Cardiomyopathies; Histones; Humans; Methylation; Oxidative Stress; Protein Processing, Post-Translational
PubMed: 35770643
DOI: No ID Found