Mechanisms of cardiac dysfunction in diabetic cardiomyopathy: molecular abnormalities and phenotypical variants

2022 ◽  
Author(s):  
Francesca Romana Prandi ◽  
Isabella Evangelista ◽  
Domenico Sergi ◽  
Alberto Palazzuoli ◽  
Francesco Romeo
Keyword(s):  
Diabetic Cardiomyopathy ◽  
Cardiac Dysfunction ◽  
Molecular Abnormalities

Kir6.1 improves cardiac dysfunction in diabetic cardiomyopathy via the AKT-Foxo1 signaling pathway

2020 ◽  
Author(s):  
Jinxin Wang ◽  
Jing Bai ◽  
Peng Duan ◽  
Hao Wang ◽  
Yang Li ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Signaling Pathway ◽  
Diabetic Cardiomyopathy ◽  
Cardiac Dysfunction ◽  
Diabetic Patients ◽  
Protein Levels ◽  
Inwardly Rectifying Potassium Channel ◽  
Transmission Electron ◽  
Hematoxylin And Eosin ◽  
And Function

Abstract Background: Diabetic cardiomyopathy (DCM) severely impairs the health of diabetic patients. Previous studies have shown that the expression of inwardly rectifying potassium channel 6.1 (Kir6.1) in heart mitochondria is significantly reduced in type 1 diabetes. However, whether its expression and function are changed and what role it plays in type 2 DCM have not been reported. This study investigated the role and mechanism of Kir6.1 in DCM.Methods: The cardiac function in mice was analyzed by echocardiography, ELISA, hematoxylin and eosin staining, TUNEL and transmission electron microscopy. The mitochondrial function in cardiomyocytes was measured by the oxygen consumption rate and the mitochondrial membrane potential (ΔΨm). Kir6.1 expression at the mRNA and protein levels was analyzed by quantitative real-time PCR and western blotting (WB), respectively. The protein expression of t-AKT, p-AKT, t-Foxo1, and p-Foxo1 was analyzed by WB.Results: We found that the cardiac function and the Kir6.1 expression in DCM mice were decreased. Kir6.1 overexpression improved cardiac dysfunction and upregulated the phosphorylation of AKT and Foxo1 in the DCM mouse model. Furthermore, Kir6.1 overexpression also improved cardiomyocyte dysfunction and upregulated the phosphorylation of AKT and Foxo1 in cardiomyocytes with insulin resistance. In contrast, cardiac-specific Kir6.1 knockout aggravated the cardiac dysfunction and downregulated the phosphorylation of AKT and Foxo1 in DCM mice. Furthermore, Foxo1 activation downregulated the expression of Kir6.1 and decreased the ΔΨm in cardiomyocytes. In contrast, Foxo1 inactivation upregulated the expression of Kir6.1 and increased the ΔΨm in cardiomyocytes. Chromatin immunoprecipitation assay demonstrated that the Kir6.1 promoter region contains a functional Foxo1-binding site .Conclusions: Kir6.1 improves cardiac dysfunction in DCM, probably through the AKT-Foxo1 signaling pathway. Moreover, the crosstalk between Kir6.1 and the AKT-Foxo1 signaling pathway may provide new strategies for reversing the defective signaling in DCM.

scholarly journals GW27-e1129 RSVA314 attenuates cardiac dysfunction, oxidative stress, and inflammatory in diabetic cardiomyopathy

2016 ◽  
Vol 68 (16) ◽  
pp. C40-C41
Author(s):  
Gan Shouyi ◽  
Hui Yu ◽  
Hong-xia Huang ◽  
Bing Li ◽  
Ling-Yong Zeng ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Diabetic Cardiomyopathy ◽  
Cardiac Dysfunction

scholarly journals CTRP3 attenuates cardiac dysfunction, inflammation, oxidative stress and cell death in diabetic cardiomyopathy in rats

Diabetologia ◽  
2017 ◽  
Vol 60 (6) ◽  
pp. 1126-1137 ◽  
Author(s):  
Zhen-Guo Ma ◽  
Yu-Pei Yuan ◽  
Si-Chi Xu ◽  
Wen-Ying Wei ◽  
Chun-Ru Xu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Diabetic Cardiomyopathy ◽  
Cardiac Dysfunction

scholarly journals NAD+ Redox Imbalance in the Heart Exacerbates Diabetic Cardiomyopathy

2020 ◽  
Author(s):  
Ying Ann Chiao ◽  
Akash Deep Chakraborty ◽  
Christine M. Light ◽  
Rong Tian ◽  
Junichi Sadoshima ◽  
...  
Keyword(s):  
Diabetic Cardiomyopathy ◽  
Cardiac Dysfunction ◽  
Troponin I ◽  
Therapeutic Potential ◽  
Redox Balance ◽  
Diabetic Mice ◽  
Nicotinamide Phosphoribosyltransferase ◽  
Redox Imbalance ◽  
Nadh Ratio ◽  
Regulate Protein

AbstractBackgroundDiabetes is a risk factor of heart failure and promotes cardiac dysfunction. Diabetic tissues are associated with NAD+ redox imbalance; however, the hypothesis that NAD+ redox imbalance leads to dysfunction of diabetic hearts has not been tested. In this study, we employed mouse models with altered NAD+ redox balance to test the hypothesis.Methods and ResultsDiabetes was induced in C57BL/6 mice by streptozotocin injections, and diabetic cardiomyopathy (DCM) was allowed to develop for 16 weeks. Diabetic stress led to cardiac dysfunction and lowered NAD+/NADH ratio. This diabetogenic regimen was administered to cardiac-specific knockout mice of complex I subunit Ndufs4 (cKO), a model with lowered cardiac NAD+/NADH ratio without baseline dysfunction. Cardiac NAD+ redox imbalance in cKO hearts exacerbated systolic and diastolic dysfunction of diabetic mice in both sexes. Collagen levels and transcript analyses of fibrosis and extracellular matrix-dependent pathways did not show change in diabetic cKO hearts, suggesting that the exacerbated cardiac dysfunction was likely due to cardiomyocyte dysfunction. We found that cardiac NAD+ redox imbalance promoted superoxide dismutase 2 (SOD2) acetylation, protein oxidation, induced troponin I S150 phosphorylation and impaired energetics in diabetic cKO hearts. Importantly, elevation of cardiac NAD+ levels by nicotinamide phosphoribosyltransferase (NAMPT) normalized NAD+ redox balance, over-expression alleviated cardiac dysfunction and reversed pathogenic mechanisms in diabetic mice.ConclusionOur results show that NAD+ redox imbalance to regulate protein acetylation and phosphorylation is a critical mediator of the progression of DCM, and suggest the therapeutic potential of harnessing NAD+ metabolism in DCM.

scholarly journals Speckle-Tracking Echocardiography is Preferable Measurement for Detecting the Early and Subtle Alterations of Cardiac Dysfunction in Diabetic Rats

2021 ◽  
Author(s):  
Zhiyan Chen ◽  
Yanchao Qi ◽  
Lijie Wang ◽  
Meifang Ma ◽  
Na Li ◽  
...  
Keyword(s):  
Early Detection ◽  
Strain Rate ◽  
Diabetic Cardiomyopathy ◽  
Cardiac Dysfunction ◽  
Speckle Tracking ◽  
Circumferential Strain ◽  
Speckle Tracking Echocardiography ◽  
Diabetic Rats ◽  
Left Ventricular ◽  
Global Circumferential Strain

Abstract BackgroundMyocardial damage caused by diabetic cardiomyopathy results in cardiac structural and functional abnormalities. Our previous studies have demonstrated that inhibiting RhoA/ROCK signaling pathway improved the structural abnormalities. The early detection of cardiac functional alterations accompanied by structural changes during therapy may facilitate better understanding on the pathophysiologic progress and guiding diabetic cardiomyopathy treatment. This study aimed to identify the optimal diagnostic measures for the early and subtle alterations of cardiac dysfunction in Type 2 diabetes mellitus rats.MethodsTwenty-four male Wistar rats were randomly divided into four groups and treated for 4 weeks: CON (control rats), DM (diabetic rats), DMF (DM + fasudil 10mg/kg/d) and CONF (CON + fasudil 10mg/kg/d). Left ventricular (LV) structure was quantified by histological staining and transmission electron microscopy. LV function and myocardial deformation were performed by high-frequency echocardiography.ResultsMyocardial hypertrophy and fibrosis were increased in diabetic rats and were remarkably alleviated in the DMF group. The diabetic rats had impaired LV performance evidenced by significant reduction of EF, FS and MV E/A, 26%, 34% and 20% respectively, while ROCK inhibition failed to improve the conventional ultrasonic parameters. However, the cardiac time intervals (CTI) parameters and speckle-tracking echocardiography (STE) parameters were significantly improved in the DMF group compared with the DM group (isovolumic contraction time, IVCT: P = 0.029; myocardial performance index, MPI: P = 0.037; fractional area change, FAC: P < 0.001; global circumferential strain, GCS: P = 0.003; global circumferential strain rate, GCSR: P = 0.021). Combining ROC curves with linear regression analysis, STE parameters were characterized by both the optimal predictions for cardiac damage [AUC (95% CI): FAC, 0.927 (0.744 to 0.993); GCS, 0.819 (0.610 to 0.945); GCSR, 0.899 (0.707 to 0.984)] and the strong correlations with cardiac fibrosis (FAC, r = -0.825; GCS, r = 0.772; GCSR, r = 0.829).ConclusionThe results suggest that STE strain and strain rate are preferable indicators of the early detection of subtle alterations in cardiac dysfunction and the quantitation of therapeutic efficacy in diabetic cardiomyopathy.

scholarly journals Autophagy inhibition enables Nrf2 to exaggerate the progression of diabetic cardiomyopathy in mice

2020 ◽  
Author(s):  
Ada Admin ◽  
Huimei Zang ◽  
Weiwei Wu ◽  
Lei Qi ◽  
Wenbin Tan ◽  
...  
Keyword(s):  
Diabetic Cardiomyopathy ◽  
Cardiac Dysfunction ◽  
Antioxidant Defense ◽  
Myocardial Damage ◽  
Related Factor ◽  
Nrf2 Knockout ◽  
Underlying Mechanisms ◽  
Autophagy Inhibition ◽  
And Oxidative Stress

Nuclear factor-erythroid factor 2-related factor 2 (Nrf2) may either ameliorate or worsen diabetic cardiomyopathy. However, the underlying mechanisms are poorly understood. Herein we report a novel mechanism of Nrf2-mediated myocardial damage in type 1 diabetes (T1D). Global Nrf2 knockout (Nrf2KO) hardly affected the onset of cardiac dysfunction induced by T1D but slowed down its progression in mice independent of sex. In addition, Nrf2KO inhibited cardiac pathological remodeling, apoptosis and oxidative stress associated with both onset and advancement of cardiac dysfunction in T1D. Such Nrf2-mediated progression of diabetic cardiomyopathy was confirmed by cardiomyocyte-restricted (CR) Nrf2 transgenic (Tg) approach in mice. Moreover, cardiac autophagy inhibition via CR KO of autophagy related 5 gene (CR-Atg5KO) led to early onset and accelerated development of cardiomyopathy in T1D, and CR-Atg5KO-induced adverse phenotypes were rescued by additional Nrf2KO. Mechanistically, chronic T1D leads to glucolipotoxicity inhibiting autolysosome efflux, which in turn intensifies Nrf2-driven transcription to fuel lipid peroxidation while inactivating Nrf2-mediated antioxidant defense and impairing Nrf2-coordinated iron metabolism, thereby leading to ferroptosis in cardiomyocytes. These results demonstrate that diabetes over time causes autophagy deficiency, which turns off Nrf2-mediated defense while switching on Nrf2-operated pathological program toward ferroptosis in cardiomyocytes, thereby worsening the progression of diabetic cardiomyopathy.

Role of catecholamines in the pathogenesis of diabetic cardiomyopathy

2019 ◽  
Vol 97 (9) ◽  
pp. 815-819 ◽  
Author(s):  
Naranjan S. Dhalla ◽  
Pallab K. Ganguly ◽  
Sukhwinder K. Bhullar ◽  
Paramjit S. Tappia
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Nervous System ◽  
Sympathetic Nervous System ◽  
Diabetic Cardiomyopathy ◽  
Cardiac Dysfunction ◽  
Oxidation Products ◽  
Sympathetic Nervous ◽  
Myocardial Gene Expression

Although the sympathetic nervous system plays an important role in the regulation of cardiac function, the overactivation of the sympathetic nervous system under stressful conditions including diabetes has been shown to result in the excessive production of circulating catecholamines as well as an increase in the myocardial concentration of catecholamines. In this brief review, we provide some evidence to suggest that the oxidation products of catecholamines such as aminochrome and oxyradicals, lead to metabolic derangements, Ca2+-handling abnormalities, increase in the availability of intracellular free Ca2+, as well as activation of proteases and changes in myocardial gene expression. These alterations due to elevated levels of circulatory catecholamines are associated with oxidative stress, subcellular remodeling, and the development of cardiac dysfunction in chronic diabetes.

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