Abstract
Regulated/activated protein kinase (PRAK) plays a crucial role in modulating biological function. However, the role of PRAK in mediating cardiac dysfunction and metabolic disorders remains unclear. We examined the effects of deletion of PRAK on modulating cardiac function and insulin resistance in mice exposed to a high-fat diet (HFD). Wild-type and PRAK−/− mice at 8 weeks old were exposed to either chow food or HFD for a consecutive 16 weeks. Glucose tolerance tests and insulin tolerance tests were employed to assess insulin resistance. Echocardiography was employed to assess myocardial function. Western blot was used to determine the molecular signaling involved in phosphorylation of IRS-1, AMPKα, ERK-44/42, and irisin. Real time-PCR was used to assess the hypertrophic genes of the myocardium. Histological analysis was employed to assess the hypertrophic response, interstitial myocardial fibrosis, and apoptosis in the heart. Western blot was employed to determine cellular signaling pathway. HFD-induced metabolic stress is indicated by glucose intolerance and insulin intolerance. PRAK knockout aggravated insulin resistance, as indicated by glucose intolerance and insulin intolerance testing as compared with wild-type littermates. As compared with wild-type mice, hyperglycemia and hypercholesterolemia were manifested in PRAK-knockout mice following high-fat diet intervention. High-fat diet intervention displayed a decline in fractional shortening and ejection fraction. However, deletion of PRAK exacerbated the decline in cardiac function as compared with wild-type mice following HFD treatment. In addition, PRAK knockout mice enhanced the expression of myocardial hypertrophic genes including ANP, BNP, and βMHC in HFD treatment, which was also associated with an increase in cardiomyocyte size and interstitial fibrosis. Western blot indicated that deletion of PRAK induces decreases in phosphorylation of IRS-1, AMPKα, and ERK44/42 as compared with wild-type controls. Our finding indicates that deletion of PRAK promoted myocardial dysfunction, cardiac remodeling, and metabolic disorders in response to HFD.
Highlights
The mitogen-activated protein (MAP) kinase pathway has been identified to contribute critically to the regulation of metabolic stress and tissue injury in multiple tissues [1]
In order to determine the effect of deletion of p38 regulated/activated kinase (PRAK) on insulin resistance, we implemented glucose tolerance tests and insulin tolerance tests
Deletion of PRAK exacerbated the magnitude of insulin intolerance, which is indicated by Insulin tolerance test (ITT) and area under the curve (AUC) that were enhanced by depletion of PRAK in response to high-fat diet (HFD)
Summary
The mitogen-activated protein (MAP) kinase pathway has been identified to contribute critically to the regulation of metabolic stress and tissue injury in multiple tissues [1]. Depletion of PRAK in mice promotes 7,12-dimethylbenz[a]-anthracene (DMBA)-induced skin carcinogenesis, coinciding with development of compromised senescence [15]. It remains unknown if PRAK is essential to modulating myocardial function and metabolic stress in response to high-fat diet-induced diabetes. Our results indicate that deletion of PRAK promoted myocardial dysfunction, enhanced myocardial remodeling, suppressed the insulin signaling pathway, and elicited insulin resistance in response to HFD, suggesting that PRAK is critical to modulating cardiac function and remodeling in mice exposed to HFD
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