The mechanisms underlying the myocardial protection of valsartan against ischemia/reperfusion (I/R) injury are complicated and remain unclear. The aim of this study was to investigate whether autophagy machinery was involved in the protection against I/R injury that is induced by valsartan. In vivo rat hearts were subjected to ischemia by 30 min ligation of the left anterior descending coronary artery, followed by a 120 min reperfusion. 3‑methyladenine (3‑MA), a specific inhibitor on autophagic sequestration, was used to inhibit autophagy. The hemodynamics, infarct size of the ventricle and LC3B protein were measured. Western blot analysis was performed to investigate the mechanism by which autophagy was induced by valsartan. Valsartan preconditioning resulted in a significant decrease in infarct size and induced autophagy in the rat heart subjected to I/R injury. The hemodynamics assay showed that the valsartan‑induced cardiac functional recovery was attenuated by 3‑MA. By contrast, 3‑MA decreased the improvement induced by valsartan on the histology and infarction of the rat heart subjected to I/R injury. Valsartan preconditioning induced autophagy via the AKT/mTOR/S6K pathway, independent of Beclin1. In conclusion, valsartan preconditioning induced autophagy via the AKT/mTOR/S6K pathway, which contributed to the myocardial protection against I/R injury.
Diabetic cardiomyopathy is a major cause of morbidity and mortality among diabetic patients. Endoplasmic reticulum (ER) stress has been involved in diabetic cardiomyopathy. Accumulation of endogenous nitric oxide synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA) is associated with diabetic cardiovascular complications. This study was to determine whether ADMA accumulation contributes to diabetic cardiomyopathy and whether its mechanism is related to ER stress in streptozotocin-induced diabetic rats and cultured rat cardiomyocytes. Cardiac function was measured by M-echocardiography. ER stress was reflected by transcription of glucose-regulated protein78, phosphorylation of eukaryotic initiation factor 2α kinase, splicing of X box-binding protein-1 mRNA and expression of C/EBP homologues protein. Changes of ADMA signal pathway were evaluated by ADMA and nitric oxide contents, NOS and dimethylarginine dimethylaminohydrolase activities, as well as their protein expression. The levels of ADMA in serum and myocardium were significantly elevated in diabetic rats compared to control rats. This elevation was associated with left ventricular diastolic and systolic dysfunction of diabetic rats in comparison with control rats. Furthermore, ADMA accumulation was not only coupled with the disorder of ADMA signal pathway, but also tied to ER stress and oxidative stress in myocardium of diabetic rats. Treatment of diabetic rats with antioxidant N-acetylcysteine could reduce oxidative stress and ER stress, but also ameliorate cardiac dysfunction of diabetic rats. Similar results to diabetic rats were observed in the exogenous NOS inhibitor-treated normal rats and ADMA-incubated cardiomyocytes. These results indicate that endogenous ADMA accumulation plays a pivotal role in the development of diabetic cardiomyopathy, and the underlying mechanism is close related to ER stress and oxidative stress.
Disclosure
Y. Xiong: None. Y. He: None. W. Fang: None. Y. Lei: None. Y. Lin: None. Z. He: None.
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