Simvastatin Improves Cardiac Hypertrophy In Diabetic Rats Through Attenuation Of Oxidative Stress And Inflammation Induced By Calpain-1

ObjectiveTo explore the effect of simvastatin on myocardial hypertrophy in diabetic rats induced by streptozotocin?STZ?,and further explore its potential mechanism of action,providing a new direction for the treatment of diabetic cardiomyopathy?DCM?.MethodsForty male healthy Sprague-Dawley?SD?rats were randomly assigned to 4groups:the control group?CON group?,diabetes model group?STZ group?,and simvastatin low-dose treatment(10 mg·kg^-1)group?STZ+SIM10 group?,simvastatin high-dose treatment(20 mg·kg^-1)group?STZ+SIM20 group?.After5 days of intraperitoneal injection of streptozotocin(50 mg·kg^-1),we detected random blood glucose in the diabetic group and simvastatin-administered group.When the blood glucose level was?15 mmol/L,the rat model was considered successful.Simvastatin was given to the corresponding concentration of simvastatin for 12 weeks.The model group and the CON group were given the same volume of normal saline.The body weight,left ventricular weight and whole heart weight were weighed.Left ventricle mass index?LVMI?and Heart mass index?HMI?;Kits was used to detect triglyceride,blood glucose,total cholesterol and calpain activity in rats;Real-time PCR was used to detected BNP,ANP mRNA expression;HE staining was used to observe the histomorphological differences of myocardial tissue;Immunohistochemistry was used to detect the expression of p65 in myocardial tissue;DHE?Dihydroethidium?staining was used to observe the level of superoxide anion in each group;The levels of Interleukin-6?IL-6?and tumor necrosis factor-??TNF-??were detected by enzyme-linked immunosorbent assay?ELISA?kit.Western Blot was used to detect the expression of ANP,BNP,iNOS,eNOS,TNF-?,ICAM-1,VCAM-1,IL-6,I?B?,calpain-1 and p65 protein.ResultsCompared with the CON group,after STZ modeling,?1?body weight decreased,LVMI,HMI of rats increased,ANP,BNP mRNA and protein expression increased?P<0.05?;?2?blood glucose,total cholesterol and triglyceride levels in serum of rats increased significantly?P<0.05?;?3?HE staining results showed a large number of myocardial cell disorder,cell hypertrophy,accompanied by inflammatory cell infiltration and other lesions in rat myocardial tissue;?4?DHE staining results showed a large increase of superoxide anion in rat myocardial tissue;?5?The content of serum TNF-??P<0.01?and IL-6 increased?P<0.05?;?6?The expression of eNOS,cytoplasmic IkB?,p65 protein decreased,and the expression of iNOS,VCAM-1,IL-6,TNF-?,ICAM-1 and nuclear p65 protein increased?P<0.05?;?7?The expression of calpain-1 protein in cardiac tissue is increased,and the activity of calpain is enhanced?P<0.05?.Compared with the STZ group,after treatment with simvastatin,?1?body weight increased,HMI,LVMI decreased,ANP,BNP mRNA and protein expression decreased?P<0.05?;?2?serum blood glucose,cholesterol and triglyceride content decreased significantly?P<0.05?;?3?HE staining observed that simvastatin significantly reversed the morphological changes shown in the model group;?4?The content of superoxide anion in the heart tissue of rats was decreased.?5?The eNOS,cytoplasmic p65 and IkB?in heart tissue increased,iNOS,ICAM-1,IL-6,VCAM-1,TNF-?,and nuclear p65 protein expression decreased?P<0.05?;?6?calpain-1 protein expression decreased,calpain activity decreased?P<0.05?;?7?The expression of TNF-?,IL-6 serum levels decreased?P<0.05?.ConclusionSimvastatin improved myocardial hypertrophy in STZ-induced diabetic rats,its mechanism may be related to the reduction of calpain-1 mediated oxidative stress and inflammation by simvastatin.