Akt is a critical node of acute myocardial insulin resistance and cardiac dysfunction after cardiopulmonary bypass

Myocardial insulin resistance contributes to heart failure in response to pathological stresses, therefore, a therapeutic strategy to maintain cardiac insulin pathways requires further investigation. We demonstrated that insulin receptor substrate 1 (IRS1) was reduced in failing mouse hearts post-myocardial infarction (MI) and failing human hearts. The mice manifesting severe cardiac dysfunction post-MI displayed elevated mir128-3p in the myocardium. Ischemia-upregulated mir128-3p promoted Irs1 degradation. Using rat cardiomyocytes and human-induced pluripotent stem cell-derived cardiomyocytes, we elucidated that mitogen-activated protein kinase 7 (MAPK7, also known as ERK5)-mediated CCAAT/enhancer-binding protein beta (CEBPβ) transcriptionally represses mir128-3p under hypoxia. Therapeutically, functional studies demonstrated gene therapy-delivered cardiac-specific MAPK7 restoration or overexpression of CEBPβ impeded cardiac injury after MI, at least partly due to normalization of mir128-3p. Furthermore, inhibition of mir128-3p preserved Irs1 and ameliorated cardiac dysfunction post-MI. In conclusion, we reveal that targeting mir128-3p mitigates myocardial insulin resistance, thereafter slowing down the progression of heart failure post-ischemia.

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Vitamin D Deficiency in Rats Causes Cardiac Dysfunction by Inducing Myocardial Insulin Resistance

Molecular Nutrition & Food Research ◽

10.1002/mnfr.201900109 ◽

2019 ◽

Vol 63 (17) ◽

pp. 1900109 ◽

Cited By ~ 4

Author(s):

Hina Lateef Nizami ◽

Parmeshwar Katare ◽

Pankaj Prabhakar ◽

Yashwant Kumar ◽

Sudheer Kumar Arava ◽

...

Keyword(s):

Insulin Resistance ◽

Vitamin D ◽

Vitamin D Deficiency ◽

Cardiac Dysfunction ◽

Myocardial Insulin Resistance

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miR-155-5p upregulation ameliorates myocardial insulin resistance via mTOR signaling in chronic alcohol drinking rats

PeerJ ◽

10.7717/peerj.10920 ◽

2021 ◽

Vol 9 ◽

pp. e10920

Author(s):

Zhaoping Li ◽

Zhenzhen Hu ◽

Yan Meng ◽

Hongzhao Xu ◽

Yali Wei ◽

...

Keyword(s):

Insulin Resistance ◽

Cardiac Function ◽

Insulin Receptor ◽

Alcohol Drinking ◽

Cardiac Dysfunction ◽

Alcohol Intake ◽

Mtor Signaling ◽

Chronic Alcohol ◽

Mtor Signaling Pathway ◽

Myocardial Insulin Resistance

Background Chronic alcohol intake is associated with an increased risk of alcoholic cardiomyopathy, which may present with pathological changes such as myocardial insulin resistance, leading to ventricular dilation and cardiac dysfunction. Although a correlation between microRNA-155 (miR-155) and insulin signaling has been identified, the underlying mechanism has not been elucidated to date. The purpose of the study was to determine whether overexpression of miR-155-5p in vivo could ameliorate chronic alcohol-induced myocardial insulin resistance and cardiac dysfunction. Material and Methods Wistar rats were fed with either alcohol or water for 20 weeks to establish chronic alcohol intakes model. Then the alcohol group were divided into three groups: model group, miRNA-155 group and AAV-NC group. Rats undergoing alcohol treatment were injected with AAV-miRNA-155 (adeno-associated virus 9) or its negative control AAV-NC, respectively. Gene expression was determined by real-time PCR, and protein expression was determined by western blot. Echocardiography was performed to assess terminal cardiac function. Insulin responsiveness was determined through the quantification of phosphorylated insulin receptor substrate 1 (ser 307) and phosphorylated insulin receptor (Tyr 1185) levels. Results We found that cardiac function was attenuated in chronic alcohol intake rats, with an activated mammalian target of rapamycin (mTOR) signaling pathway, accompanied by an increase in p-IRS1(ser 307) and a decrease in p-IR (Tyr 1185) level in myocardial tissue. Also, alcohol drinking significantly up-regulated miR-155-5p level and its overexpression decreased p-IRS1 (ser 307) and increased p-IR (Tyr 1185) levels, and meanwhile inhibited the mTOR signaling pathway. Conclusion miR-155-5p upregulation ameliorates myocardial insulin resistance via the mTOR signaling in chronic alcohol drinking rats. We propose that miR-155 may serve as a novel potential therapeutic target for alcoholic heart disease.

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Role of Phosphorylated AMP-Activated Protein Kinase (AMPK) in Myocardial Insulin Resistance After Myocardial Ischemia-Reperfusion During Cardiopulmonary Bypass Surgery in Dogs

Medical Science Monitor ◽

10.12659/msm.916517 ◽

2019 ◽

Vol 25 ◽

pp. 4149-4158

Author(s):

Deng-Shen Zhang ◽

Gui-You Liang ◽

Da-Xing Liu ◽

Jie Yu ◽

Feng Wang

Keyword(s):

Insulin Resistance ◽

Cardiopulmonary Bypass ◽

Protein Kinase ◽

Myocardial Ischemia ◽

Bypass Surgery ◽

Ischemia Reperfusion ◽

Myocardial Ischemia Reperfusion ◽

Myocardial Insulin Resistance ◽

Amp Activated Protein Kinase

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Liver steatosis coexists with myocardial insulin resistance and coronary dysfunction in patients with type 2 diabetes

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00604.2005 ◽

2006 ◽

Vol 291 (2) ◽

pp. E282-E290 ◽

Cited By ~ 97

Author(s):

Riikka Lautamäki ◽

Ronald Borra ◽

Patricia Iozzo ◽

Markku Komu ◽

Terho Lehtimäki ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Liver Steatosis ◽

Fat Content ◽

Liver Fat ◽

Liver Fat Content ◽

Artery Disease ◽

Myocardial Insulin Resistance ◽

High Liver

Nonalcoholic fatty liver (NAFL) is a common comorbidity in patients with type 2 diabetes and links to the risk of coronary syndromes. The aim was to determine the manifestations of metabolic syndrome in different organs in patients with liver steatosis. We studied 55 type 2 diabetic patients with coronary artery disease using positron emission tomography. Myocardial perfusion was measured with [15O]H2O and myocardial and skeletal muscle glucose uptake with 2-deoxy-2-[18F]fluoro-d-glucose during hyperinsulinemic euglycemia. Liver fat content was determined by magnetic resonance proton spectroscopy. Patients were divided on the basis of their median (8%) into two groups with low (4.6 ± 2.0%) and high (17.4 ± 8.0%) liver fat content. The groups were well matched for age, BMI, and fasting plasma glucose. In addition to insulin resistance at the whole body level ( P = 0.012) and muscle ( P = 0.002), the high liver fat group had lower insulin-stimulated myocardial glucose uptake ( P = 0.040) and glucose extraction rate ( P = 0.0006) compared with the low liver fat group. In multiple regression analysis, liver fat content was the most significant explanatory variable for myocardial insulin resistance. In addition, the high liver fat group had increased concentrations of high sensitivity C-reactive protein, soluble forms of E-selectin, vascular adhesion protein-1, and intercellular adhesion molecule-1 ( P < 0.05) and lower coronary flow reserve ( P = 0.02) compared with the low liver fat group. In conclusion, in patients with type 2 diabetes and coronary artery disease, liver fat content is a novel independent indicator of myocardial insulin resistance and reduced coronary functional capacity. Further studies will reveal the effect of hepatic fat reduction on myocardial metabolism and coronary function.

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Liraglutide protects cardiac function in diabetic rats through the PPARα pathway

Bioscience Reports ◽

10.1042/bsr20180059 ◽

2018 ◽

Vol 38 (2) ◽

Cited By ~ 1

Author(s):

Qian Zhang ◽

Xinhua Xiao ◽

Jia Zheng ◽

Ming Li ◽

Miao Yu ◽

...

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

Cardiac Dysfunction ◽

Diabetic Rats ◽

Left Ventricular ◽

Serum Adiponectin ◽

Diabetic Rat ◽

Lv Function ◽

High Dose ◽

And Oxidative Stress

Increasing evidence shows that diabetes causes cardiac dysfunction. We hypothesized that a glucagon-like peptide-1 (GLP-1) analog, liraglutide, would attenuate cardiac dysfunction in diabetic rats. A total of 24 Sprague–Dawley (SD) rats were divided into two groups fed either a normal diet (normal, n=6) or a high-fat diet (HFD, n=18) for 4 weeks. Then, the HFD rats were injected with streptozotocin (STZ) to create a diabetic rat model. Diabetic rats were divided into three subgroups receiving vehicle (diabetic, n=6), a low dose of liraglutide (Llirag, 0.2 mg/kg/day, n=6), or a high dose of liraglutide (Hlirag, 0.4 mg/kg/day, n=6). Metabolic parameters, systolic blood pressure (SBP), heart rate (HR), left ventricular (LV) function, and whole genome expression of the heart were determined. Diabetic rats developed insulin resistance, increased blood lipid levels and oxidative stress, and impaired LV function, serum adiponectin, nitric oxide (NO). Liraglutide improved insulin resistance, serum adiponectin, NO, HR, and LV function and reduced blood triglyceride (TG), total cholesterol (TC) levels, and oxidative stress. Moreover, liraglutide increased heart nuclear receptor subfamily 1, group H, member 3 (Nr1h3), peroxisome proliferator activated receptor (Ppar) α (Pparα), and Srebp expression and reduced diacylglycerol O-acyltransferase 1 (Dgat) and angiopoietin-like 3 (Angptl3) expression. Liraglutide prevented cardiac dysfunction by activating the PPARα pathway to inhibit Dgat expression and oxidative stress in diabetic rats.

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Abstract 15931: Glycogen Synthase Kinase-3α Plays a Critical Role in the Development of Cardiac Dysfunction During Obesity and Insulin Resistance Through Phosphorylation of Peroxisome Proliferator-Activated Receptor α

Circulation ◽

10.1161/circ.130.suppl_2.15931 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Michinari Nakamura ◽

Peiyong Zhai ◽

Junichi Sadoshima

Keyword(s):

Insulin Resistance ◽

Cardiac Hypertrophy ◽

Diastolic Dysfunction ◽

Cardiac Dysfunction ◽

Lipid Accumulation ◽

Glycogen Synthase ◽

Critical Role ◽

Cardiac Metabolism ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor

Obesity and insulin resistance (IR) lead to impaired cardiac metabolism, resulting in cardiac dysfunction. However, the underlying mechanisms responsible for the development of cardiac dysfunction remain poorly understood. PPARα serves as a key regulator of fatty acid (FA) metabolism in the heart. GSK-3α, a serine/threonine kinase, was dephosphorylated at S21 and activated (2.0 fold, p<0.05) in the hearts of obese mice fed a high-fat diet (HFD) and ob/ob mice. To evaluate the functional significance of GSK-3α upregulation, wild-type (WT) and cardiac specific GSK-3α heterozygous knockout (cGSK-3α HKO) mice were fed a HFD for up to 14 weeks. There was no difference in the food intake or body weight change between WT and cGSK-3α HKO mice. However, cardiac hypertrophy and diastolic dysfunction observed in WT mice were significantly ameliorated in cGSK-3α HKO mice after HFD feeding (8.1± 0.6 and 6.5±0.5, LVW/TL; 24.8±0.9 and 16.6±0.8, deceleration time (DT), all p<0.05). FA oxidation (FAO) (0.81 fold) and ectopic lipid accumulation (Oil Red O staining) were significantly decreased in cGSK-3α HKO mice than in WT mice after HFD feeding. GSK-3α, but not GSK-3β, directly interacted with and phosphorylated PPARα at the ligand binding domain in cardiomyocytes (CMs) and in the heart. PPARα phosphorylation in the heart was significantly increased (2.1 fold, p<0.05) in response to HFD, but it was attenuated in cGSK-3α HKO mice (0.74 fold, p<0.05). Fenofibrate, a PPARα ligand, inhibited GSK-3α-induced PPARα phosphorylation (0.81 fold, p<0.05), reduced ectopic lipid accumulation, FAO (0.84 fold, p<0.05), and attenuated diastolic dysfunction (25.5±3.1 and 18.6±2.5, DT; 0.16±0.04 and 0.08±0.02, EDPVR, all p<0.05) in the heart of HFD fed mice. Collectively, these results suggest that GSK-3α increases PPARα activity through phosphorylation of PPARα, which is inhibited by Fenofibrate. Activation of GSK-3α and consequent phosphorylation of PPARα during obesity and IR could play an important role in the development of cardiac hypertrophy and diastolic dysfunction. Synthetic PPARα ligands inhibit GSK-3α-mediated phosphorylation of PPARα, thereby paradoxically attenuating excessive FA metabolism in cardiomyocytes.

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