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Redox Biology Aug 2023Brain and muscle arnt-like protein 1 (Bmal1) is a crucial transcription factor, regulating circadian rhythm and involved in multiple heart diseases. However, it is...
Brain and muscle arnt-like protein 1 (Bmal1) is a crucial transcription factor, regulating circadian rhythm and involved in multiple heart diseases. However, it is unknown whether Bmal1 promotes diabetic cardiomyopathy (DCM) pathogenesis. The objective of this investigation was to ascertain the vital role of Bmal1 in the progression of DCM. Mice with T2D and H9c2 cardiomyoblasts exposed to high glucose and palmitic acid (HGHP) were used. Cardiomyocyte-specific knockout mouse of Bmal1 (CKB) was also generated, and cardiac Bmal1 was overexpressed in type 2 diabetes (T2D) mice using an adeno-associated virus. Bmal1 gene recombinant adenovirus was used to either knockdown or overexpress in H9c2 cardiomyoblasts. Bmal1 expression was significantly altered in diabetic mice hearts. Bmal1 downregulation in CKB and T2D mice heart accelerated cardiac hypertrophy and diastolic dysfunction, while Bmal1 overexpression ameliorated these pathological changes in DCM mice. Furthermore, DCM mice had significant mitochondrial ultrastructural defects, reactive oxygen species accumulation, and apoptosis, which could be alleviated by overexpressing Bmal1. In H9c2 cardiomyoblasts, genetic downregulation of Bmal1 or HGHP markedly decreased the binding of Bcl2 to IP3R, thus increasing Ca release to mitochondria through mitochondria-associated endoplasmic reticulum membranes. Importantly, chromatin immunoprecipitation revealed Bmal1 could bind directly to the Bcl2 gene promoter region. Bmal1 overexpression augmented the Bmal1/Bcl2 binding, enhancing the inhibition of Bcl2 on IP3R activity, thus alleviating mitochondrial Ca overload and subsequent cell apoptosis. These results show that Bmal1 is involved in the DCM development through Bcl2/IP3R-mediated mitochondria Ca overload. Therapy targeting the circadian clock (Bmal1) can treat DCM.
Topics: Animals; Mice; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Down-Regulation; Mice, Knockout; Mitochondria
PubMed: 37356134
DOI: 10.1016/j.redox.2023.102788 -
Progress in Cardiovascular Diseases 2019The prevalence of Type 2 diabetes mellitus (T2DM) has reached pandemic proportions. T2DM frequently causes macrovascular and/or microvascular pathologic changes and... (Review)
Review
The prevalence of Type 2 diabetes mellitus (T2DM) has reached pandemic proportions. T2DM frequently causes macrovascular and/or microvascular pathologic changes and thereby increases the risks for the development of myocardial infarction, heart failure, stroke, renal failure, and reduced survival. This article describes the important interactions between T2DM, heart failure, and renal dysfunction, forming vicious circles. The interruption of these circles represents important therapeutic goals.
Topics: Comorbidity; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Diabetic Nephropathies; Female; Heart Failure; Humans; Male; Prevalence; Prognosis; Renal Insufficiency, Chronic; Severity of Illness Index; Survival Analysis; United States
PubMed: 31377223
DOI: 10.1016/j.pcad.2019.07.003 -
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 -
Experimental & Molecular Medicine Sep 2023Autophagy plays an important role in the development of diabetic cardiomyopathy. Cellular repressor of E1A-stimulated genes 1 (CREG1) is an important myocardial...
Autophagy plays an important role in the development of diabetic cardiomyopathy. Cellular repressor of E1A-stimulated genes 1 (CREG1) is an important myocardial protective factor. The aim of this study was to investigate the effects and mechanisms of CREG1 in diabetic cardiomyopathy. Male C57BL/6 J mice, Creg1 transgenic mice and cardiac-specific knockout mice were used to establish a type 2 diabetes model. Small animal ultrasound, Masson's staining and western blotting were used to evaluate cardiac function, myocardial fibrosis and autophagy. Neonatal mouse cardiomyocytes (NMCMs) were stimulated with palmitate, and the effects of CREG1 on NMCMs autophagy were examined. CREG1 deficiency exacerbated cardiac dysfunction, cardiac hypertrophy and fibrosis in mice with diabetic cardiomyopathy, which was accompanied by exacerbated autophagy dysfunction. CREG1 overexpression improved cardiac function and ameliorated cardiac hypertrophy and fibrosis in diabetic cardiomyopathy by improving autophagy. CREG1 protein expression was decreased in palmitate-induced NMCMs. CREG1 knockdown exacerbated cardiomyocyte hypertrophy and inhibited autophagy. CREG1 overexpression inhibited cardiomyocyte hypertrophy and improved autophagy. LAMP2 overexpression reversed the effect of CREG1 knockdown on palmitate-induced inhibition of cardiomyocyte autophagy. CREG1 inhibited LAMP2 protein degradation by inhibiting the protein expression of F-box protein 27 (FBXO27). Our findings indicate new roles of CREG1 in the development of diabetic cardiomyopathy.
Topics: Animals; Male; Mice; Autophagy; Cardiomegaly; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Fibrosis; Mice, Inbred C57BL; Mice, Knockout; Myocytes, Cardiac; Lysosomal-Associated Membrane Protein 2; F-Box Proteins; Repressor Proteins
PubMed: 37658156
DOI: 10.1038/s12276-023-01081-2 -
Nature Reviews. Cardiology Apr 2021Diabesity is a term used to describe the combined adverse health effects of obesity and diabetes mellitus. The worldwide dual epidemic of obesity and type 2 diabetes is... (Review)
Review
Diabesity is a term used to describe the combined adverse health effects of obesity and diabetes mellitus. The worldwide dual epidemic of obesity and type 2 diabetes is an important public health issue. Projections estimate a sixfold increase in the number of adults with obesity in 40 years and an increase in the number of individuals with diabetes to 642 million by 2040. Increased adiposity is the strongest risk factor for developing diabetes. Early detection of the effects of diabesity on the cardiovascular system would enable the optimal implementation of effective therapies that prevent atherosclerosis progression, cardiac remodelling, and the resulting ischaemic heart disease and heart failure. Beyond conventional imaging techniques, such as echocardiography, CT and cardiac magnetic resonance, novel post-processing tools and techniques provide information on the biological processes that underlie metabolic heart disease. In this Review, we summarize the effects of obesity and diabetes on myocardial structure and function and illustrate the use of state-of-the-art multimodality cardiac imaging to elucidate the pathophysiology of myocardial dysfunction, prognosticate long-term clinical outcomes and potentially guide treatment strategies.
Topics: Adult; Child; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Heart Diseases; Humans; Myocardium; Obesity; United States
PubMed: 33188304
DOI: 10.1038/s41569-020-00465-5 -
Circulation Research Nov 2020Diabetic heart disease (DHD) is a debilitating manifestation of type 2 diabetes mellitus. Exercise has been proposed as a potential therapy for DHD, although the...
RATIONALE
Diabetic heart disease (DHD) is a debilitating manifestation of type 2 diabetes mellitus. Exercise has been proposed as a potential therapy for DHD, although the effectiveness of exercise in preventing or reversing the progression of DHD remains controversial. Cardiac function is critically dependent on the preservation of coronary vascular function.
OBJECTIVE
We aimed to elucidate the effectiveness and mechanisms by which exercise facilitates coronary and cardiac-protection during the onset and progression of DHD.
METHODS AND RESULTS
Diabetic db/db and nondiabetic mice, with or without underlying cardiac dysfunction (16 and 8 weeks old, respectively) were subjected to either moderate-intensity exercise or high-intensity exercise for 8 weeks. Subsequently, synchrotron microangiography, immunohistochemistry, Western blot, and real-time polymerase chain reaction were used to assess time-dependent changes in cardiac and coronary structure and function associated with diabetes mellitus and exercise and determine whether these changes reflect the observed changes in cardiac-enriched and vascular-enriched microRNAs (miRNAs). We show that, if exercise is initiated from 8 weeks of age, both moderate-intensity exercise and high-intensity exercise prevented the onset of coronary and cardiac dysfunction, apoptosis, fibrosis, microvascular rarefaction, and disruption of miRNA signaling, as seen in the nonexercised diabetic mice. Conversely, the cardiovascular benefits of moderate-intensity exercise were absent if the exercise was initiated after the diabetic mice had already established cardiac dysfunction (ie, from 16 weeks of age). The experimental silencing or upregulation of miRNA-126 activity suggests the mechanism underpinning the cardiovascular benefits of exercise were mediated, at least in part, through tissue-specific miRNAs.
CONCLUSIONS
Our findings provide the first experimental evidence for the critical importance of early exercise intervention in ameliorating the onset and progression of DHD. Our results also suggest that the beneficial effects of exercise are mediated through the normalization of cardiovascular-enriched miRNAs, which are dysregulated in DHD.
Topics: Animals; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Disease Models, Animal; Exercise Therapy; Female; Fibrosis; Gene Expression Regulation; Male; Mice; MicroRNAs; Myocardium; Physical Conditioning, Animal; Running; Signal Transduction; Time Factors; Ventricular Function, Left; Ventricular Remodeling
PubMed: 32907486
DOI: 10.1161/CIRCRESAHA.120.317604 -
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