MicroRNA-184 alleviates insulin resistance in cardiac myocytes and high fat diet-induced cardiac dysfunction in mice through the LPP3/DAG pathway

Obesity is associated with cardiac insulin resistance and contractile dysfunction, which contribute to the development of heart failure. The RhoA-Rho kinase (ROCK) pathway has been reported to modulate insulin resistance, but whether it is implicated in obesity-induced cardiac dysfunction is not known. To test this, wild-type (WT) and ROCK2+/− mice were fed normal chow or a high-fat diet (HFD) for 17 wk. Whole body insulin resistance, determined by an insulin tolerance test, was observed in HFD-WT, but not HFD-ROCK2+/−, mice. The echocardiographically determined myocardial performance index, a measure of global systolic and diastolic function, was significantly increased in HFD-WT mice, indicating a deterioration of cardiac function. However, no change in myocardial performance index was found in hearts from HFD-ROCK2+/− mice. Speckle-tracking-based strain echocardiography also revealed regional impairment in left ventricular wall motion in hearts from HFD-WT, but not HFD-ROCK2+/−, mice. Activity of ROCK1 and ROCK2 was significantly increased in hearts from HFD-WT mice, and GLUT4 expression was significantly reduced. Insulin-induced phosphorylation of insulin receptor substrate (IRS) Tyr612, Akt, and AS160 was also impaired in these hearts, while Ser307 phosphorylation of IRS was increased. In contrast, the increase in ROCK2, but not ROCK1, activity was prevented in hearts from HFD-ROCK2+/− mice, and cardiac levels of TNFα were reduced. This was associated with normalization of IRS phosphorylation, downstream insulin signaling, and GLUT4 expression. These data suggest that increased activation of ROCK2 contributes to obesity-induced cardiac dysfunction and insulin resistance and that inhibition of ROCK2 may constitute a novel approach to treat this condition.

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Cardioprotective Effects of Metformin and Vildagliptin in Adult Rats with Insulin Resistance Induced by a High-Fat Diet

Endocrinology ◽

10.1210/en.2012-1262 ◽

2012 ◽

Vol 153 (8) ◽

pp. 3878-3885 ◽

Cited By ~ 56

Author(s):

Nattayaporn Apaijai ◽

Hiranya Pintana ◽

Siriporn C. Chattipakorn ◽

Nipon Chattipakorn

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

Body Weight ◽

Mitochondrial Dysfunction ◽

Cardiac Dysfunction ◽

High Fat Diet ◽

Plasma Insulin ◽

High Fat ◽

Antidiabetic Drug ◽

Sympathovagal Imbalance

Insulin resistance has been shown to be associated with cardiac sympathovagal imbalance, myocardial dysfunction, and cardiac mitochondrial dysfunction. Whereas metformin is a widely used antidiabetic drug to improve insulin resistance, vildagliptin is a novel oral antidiabetic drug in a group of dipeptidyl peptidase-4 inhibitors in which its cardiac effect is unclear. This study aimed to determine the cardiovascular effects of metformin and vildagliptin in rats with insulin resistance induced by high-fat diet. Male Wistar rats were fed with either a normal diet or high-fat diet (n =24 each) for 12 wk. Rats in each group were divided into three subgroups to receive the vehicle, metformin (30 mg/kg, twice daily), or vildagliptin (3 mg/kg, once daily) for another 21 d. Heart rate variability (HRV), cardiac function, and cardiac mitochondrial function were determined and compared among these treatment groups. Rats exposed to a high-fat diet developed increased body weight, visceral fat, plasma insulin, cholesterol, oxidative stress, depressed HRV, and cardiac mitochondrial dysfunction. Metformin and vildagliptin did not alter body weight and plasma glucose levels but decreased the plasma insulin, total cholesterol, and oxidative stress levels. Although both metformin and vildagliptin attenuated the depressed HRV, cardiac dysfunction, and cardiac mitochondrial dysfunction, vildagliptin was more effective in this prevention. Furthermore, only vildagliptin prevented cardiac mitochondrial membrane depolarization caused by consumption of a high-fat diet. We concluded that vildagliptin is more effective in preventing cardiac sympathovagal imbalance and cardiac dysfunction, as well as cardiac mitochondrial dysfunction, than metformin in rats with insulin resistance induced by high-fat diet.

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