Irbesartan ameliorates diabetic cardiomyopathy by regulating protein kinase D and ER stress activation in a type 2 diabetes rat model.

Abstract

Recent studies demonstrate an important role of protein kinase D (PKD) in the cardiovascular system. However, the potential role of PKD in the pathogenesis of diabetic cardiomyopathy (DCM) remains unclear. Irbesartan has beneficial effects against diabetes-induced heart damage, while the mechanisms were still poorly understood. Our present study was designed to investigate the effects of irbesartan in DCM and whether the cardioprotective effects of irbesartan were mediated by PKD and endoplasmic reticulum (ER) stress. We induced the type 2 diabetic rat model by high fat diet and low dose streptozotocin injection. The characteristics of type 2 DCM were evaluated by metabolic tests, echocardiography and histopathology. 8-weeks administration of irbesartan (15, 30 and 45mg/kg/day) was used to evaluate the effect irbesartan in DCM. Diabetic rats revealed severe metabolic abnormalities, left ventricular dysfunction, myocardial fibrosis and apoptosis. PKD and ER stress were excessive activated in the myocardium of diabetic rats. Furthermore, cardiac fibrosis, apoptosis, diastolic dysfunction and ER stress were all significantly related to PKD activation in diabetic rats. Irbesartan treatment attenuated the activation of PKD and ER stress, which paralleled its cardioprotective effects. Our study suggests that irbesartan could ameliorate cardiac remodeling and dysfunction in type 2 diabetes, and these beneficial effects were associated with its ability to suppress the activation of PKD and ER stress.

• Authors: Xiangjuan Liu, Qun Xu, Xiaomeng Wang, Zhuo Zhao, Liping Zhang, Ling Zhong, Li Li, Weiqiang Kang, Yun Zhang, Zhiming Ge
• Journal: Pharmacological research (Pharmacol Res) Vol. 93 Pg. 43-51 (Mar 2015) ISSN: 1096-1186 [Electronic] Netherlands
• PMID: 25617729 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

• Biphenyl Compounds
• Cardiotonic Agents
• Tetrazoles
• protein kinase D
• Protein Kinase C
• Irbesartan

Topics

• Animals
• Biphenyl Compounds (pharmacology, therapeutic use)
• Cardiotonic Agents (pharmacology, therapeutic use)
• Diabetes Mellitus, Experimental (drug therapy, metabolism, pathology)
• Diabetes Mellitus, Type 2 (drug therapy, metabolism, pathology)
• Diabetic Cardiomyopathies (drug therapy, metabolism, pathology)
• Endoplasmic Reticulum Stress (drug effects)
• Irbesartan
• Male
• Myocardium (pathology)
• Protein Kinase C (antagonists & inhibitors, metabolism)
• Rats, Sprague-Dawley
• Tetrazoles (pharmacology, therapeutic use)