Myocardial Loss of IRS1 and IRS2 Causes Heart Failure and Is Controlled by p38α MAPK During Insulin Resistance

Qi, Yajuan; Xu, Zihui; Zhu, Qinglei; Thomas, Candice; Kumar, Rajesh; Feng, Hao; Dostal, David E.; White, Morris F.; Baker, Kenneth M.; Guo, Shaodong

doi:10.2337/db13-0095

Cited by 145 publications

(169 citation statements)

References 52 publications

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“…The beating heart requires a continuous energy supply to maintain its contractile function, and unfavorable energy substrate utilization correlates with the development of cardiomyopathy (21). In the present study, neonatal DEX administration decreased cardiac GLUT4 expression but increased PDK4 expression at the protein level, suggesting reduced cardiac glucose uptake and oxidation.…”

Section: Discussionmentioning

confidence: 45%

Effects of neonatal dexamethasone administration on cardiac recovery ability under ischemia-reperfusion in 24-wk-old rats

Jiang

et al. 2016

Pediatr Res

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Background: Evaluations of stress-induced cardiac functional alterations in adults after neonatal glucocorticoid (GC) treatment have been limited. In the present study, we evaluated adult cardiac functional recovery during postischemic reperfusion and measured cardiac gene expression involved energy metabolism in rats neonatally treated with dexamethasone (DEX). Method: Male Wistar rats were injected DEX in first 3 d after birth and controls were received saline (SAL). At 24 wk of age, insulin tolerance tests were performed, plasma lipid levels were measured, and left ventricular function and myocardial infarct size were evaluated. Expressions of genes involved in cardiac energy metabolism were measured by quantitative real-time polymerase chain reaction (PCR) and western blot. results: In 24-wk-old rats, neonatal DEX administration caused dyslipidemia, impaired cardiac recovery function and increased size of infarction, decreased cardiac expression of glucose transporter 4(GLUT4), peroxisome proliferative-activated receptor gamma coactivator 1α (PGC-1α) and ratios of phospho-forkhead box O1/forkhead box O1 (p-FoxO1/FoxO1) and phospho AMP-activated protein kinase/AMP-activated protein kinase (p-AMPK/AMPK) but increased pyruvate dehydrogenase kinase isoenzyme 4 (PDK4) expression compared with controls. conclusion: Neonatal DEX administration impairs cardiac functional recovery during reperfusion following ischemia in 24-wk-old rats. Reduced cardiac glucose utilization may contribute to the long-term detrimental effects caused by neonatal DEX treatment.

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Section: Discussionmentioning

confidence: 45%

Effects of neonatal dexamethasone administration on cardiac recovery ability under ischemia-reperfusion in 24-wk-old rats

Jiang

et al. 2016

Pediatr Res

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“…Dysregulation of IRS1 has been considered a key mechanism of insulin resistance in diabetes mellitus 20. In addition, recent findings have also linked IRS1 to the regulation of mitochondrial function in the heart 21. We therefore assessed changes at the level of IRS1.…”

Section: Resultsmentioning

confidence: 99%

Increased Protein Tyrosine Phosphatase 1B (PTP1B) Activity and Cardiac Insulin Resistance Precede Mitochondrial and Contractile Dysfunction in Pressure‐Overloaded Hearts

Nguyễn

Schwarzer

Schrepper

et al. 2018

JAHA

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BackgroundInsulin resistance in diabetes mellitus has been associated with mitochondrial dysfunction. Defects at the level of mitochondria are also characteristic of heart failure. We assessed changes in cardiac insulin response and mitochondrial function in a model of pressure overload‐induced heart failure.Methods and ResultsRats underwent aortic banding to induce pressure overload. At 10 weeks, rats showed cardiac hypertrophy and pulmonary congestion, but left ventricular dilatation and systolic dysfunction were only evident after 20 weeks. This contractile impairment was accompanied by mitochondrial dysfunction as shown by markedly reduced state 3 respiration of isolated mitochondria. Aortic banding did not affect systemic insulin response. However, insulin‐stimulated cardiac glucose uptake and glucose oxidation were significantly diminished at 10 and 20 weeks, which indicates cardiac insulin resistance starting before the onset of mitochondrial and contractile dysfunction. The impaired cardiac insulin action was related to a decrease in insulin‐stimulated phosphorylation of insulin receptor β. Consistently, we found elevated activity of protein tyrosine phosphatase 1B (PTP1B) at 10 and 20 weeks, which may blunt insulin action by dephosphorylating insulin receptor β. PTP1B activity was also significantly increased in left ventricular samples of patients with systolic dysfunction undergoing aortic valve replacement because of aortic stenosis.ConclusionsPressure overload causes cardiac insulin resistance that precedes and accompanies mitochondrial and systolic dysfunction. Activation of PTP1B in the heart is associated with heart failure in both rats and humans and may account for cardiac insulin resistance. PTP1B may be a potential target to modulate insulin sensitivity and contractile function in the failing heart.

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“…Activated IR or IGF-1R directly phosphorylates tyrosine residues on several substrates including IRS-1,-2,-3,-4, Shc, Grb-2-assocated protein (Gab1), Dock1, Cbl and APS adaptor proteins, subsequently providing specific docking sites for other signaling proteins in activating downstream protein kinases (White 2003). Mice lacking both IR and IGF-1-R in the heart displayed similar cardiac phenotype to that of H-DKO mice, in which elimination of PI-3K and Akt activity in cardiomyocytes contributed to cardiac failure and animal death (Laustsen et al 2007, Qi et al 2013. These studies revealed a fundamental mechanism for endogenous kinase activation of PI-3K and Akt that is entirely dependent on IRS-1 and -2 or insulin and IGF-1 in the heart.…”

Section: :3mentioning

confidence: 90%

“…To investigate the role of cardiac insulin signaling, we generated H-DKO mice with heart-specific deletion of both IRS-1 and IRS-2 genes using the Cre/loxP genetic approach. The mice all developed dilated cardiomyopathy and males died of heart failure at the age of 6-9 weeks with cardiac energetic deficiency, mitochondrial dysfunction, myocardial structural damage and contractile functional loss (Qi et al 2013, Riehle et al 2013. These studies revealed novel findings of insulin action in control of cardiac growth, homeostasis and survival.…”

Section: Control Of Cardiac Homeostasis By Irs-1 and Irs-2mentioning

confidence: 94%

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Insulin receptor substrate signaling controls cardiac energy metabolism and heart failure

Guo

2017

Journal of Endocrinology

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The heart is an insulin-dependent and energy-consuming organ in which insulin and nutritional signaling integrates to the regulation of cardiac metabolism, growth and survival. Heart failure is highly associated with insulin resistance, and heart failure patients suffer from the cardiac energy deficiency and structural and functional dysfunction. Chronic pathological conditions, such as obesity and type 2 diabetes mellitus, involve various mechanisms in promoting heart failure by remodeling metabolic pathways, modulating cardiac energetics and impairing cardiac contractility. Recent studies demonstrated that insulin receptor substrates 1 and 2 (IRS-1,-2) are major mediators of both insulin and insulin-like growth factor-1 (IGF-1) signaling responsible for myocardial energetics, structure, function and organismal survival. Importantly, the insulin receptor substrates (IRS) play an important role in the activation of the phosphatidylinositide-3-dependent kinase (PI-3K) that controls Akt and Foxo1 signaling cascade, regulating the mitochondrial function, cardiac energy metabolism and the renin-angiotensin system. Dysregulation of this branch in signaling cascades by insulin resistance in the heart through the endocrine system promotes heart failure, providing a novel mechanism for diabetic cardiomyopathy. Therefore, targeting this branch of IRS→PI-3K→Foxo1 signaling cascade and associated pathways may provide a fundamental strategy for the therapeutic and nutritional development in control of metabolic and cardiovascular diseases. In this review, we focus on insulin signaling and resistance in the heart and the role energetics play in cardiac metabolism, structure and function.

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Myocardial Loss of IRS1 and IRS2 Causes Heart Failure and Is Controlled by p38α MAPK During Insulin Resistance

Cited by 145 publications

References 52 publications

Effects of neonatal dexamethasone administration on cardiac recovery ability under ischemia-reperfusion in 24-wk-old rats

Effects of neonatal dexamethasone administration on cardiac recovery ability under ischemia-reperfusion in 24-wk-old rats

Increased Protein Tyrosine Phosphatase 1B (PTP1B) Activity and Cardiac Insulin Resistance Precede Mitochondrial and Contractile Dysfunction in Pressure‐Overloaded Hearts

Insulin receptor substrate signaling controls cardiac energy metabolism and heart failure

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