The Effects And Mechanisms Of Perindopril In Cardiac Dysfunction Of Diabetic Cardiomyopathy

Diabetic cardiomyopathy(DCM)is defined as myocardial injury caused by diabetes mellitus(DM).DCM is associated with significant mortality in diabetic population.It is mainly characterized by ventricular hypertrophy,diastolic and systolic dysfunction,and eventually lead to heart failure.The pathogenesis of DCM is left ventricular remodeling including cardiac apoptosis and fibrosis.The renin-angiotensin system(RAS)is activated in DM.The inhibition of RAS ameliorates left ventricular remodeling in DCM.The angiotensin-converting enzyme(ACE)inhibitors is the first line drugs for the treament of cardiovascular diseases and the prevention of cardiovascular complications in diabetes.Perindopril is a lonlg-acting angiotensin-converting enzyme(ACE)inhibitor,and it’s role in DCM remains incompletely understood.FoxO1 is an important downstream medium of PI3K/Akt signaling pathway activated in DM and induces apoptosis and fibrosis.We established diabetic cardiomyopathy rat model and investigated the role of perindopril and related pathways in DCM.ObjectiveTo investigate the role and mechanism of perindopril in left ventricular remodeling and cardiac dysfunction induced by DCM.Methods1.Animal modelForty male Sprague-Dawley rats(8 weeks in age,100-120 gwere randomized into 3 groups:control(n=10),DCM(n=15),DCM + perindopril(n=15).The control group was given a normal diet;The DCM group and DCM+perindopril group were given a high fat diet.After 4 weeks the rats of DCM group and DCM+perindopril group were injected with STZ citrate buffer(35 mg/kg)intraperitoneally.After 1 week the glucose levels of tail vein blood were measured and the rats with glucose level≥11.1mmol/L were determined to induce diabetes model successfully.8 weeks later,The control group was given a normal diet;The DCM group was received high fat diet and intragastric administration with saline;The DCM+perindopril group was received high fat diet and intragastric administration with perindopril(4 mg/kg).After 8 weeks,the cardiac function of all rats were measured.We obtained the left ventricular tissues for the following experiments.2.EchocardiographyThe cardiac function of rats was measured by two dimensional and M-mode echocardiography.3.The left ventricular remodelingThe expression of collagen was measured by masson’s trichrome staining.The myocardial apoptosis was determined by tunel’s staining.4.Western blotWestern blot was used to determine the protein expression of caspase3、p-caspase3.、collagenl.、collagenⅢ、p-Akt and p-FoxO1。5.Statistical analysisThe experiments were repeated 3 times.Data are expressed as mean±standard deviation and significance was considered at p<0.5.Results1.Perindopril ameliorated the cardiac dysfunction in DCM Compared with the control rats,the LVEF and FS of rats in DCM group decreased significantly(p<0.05),while the the LVEF and FS of rats in DCM+perindopril group increased compared with the rats in DCM group(p<0.05).2.Perindopril ameliorated the left ventricular remodeling in DCMCompared with the control rats,the cardiac apoptosis and collagen production of rats in DCM group increased(p<0.05).The results of western blot revealed increased protein expression of caspase3、collagen Ⅰ、collagen Ⅲ in DCM rats compared with control rats(p<0.05).Perindopril treatment normalized increased protein expression of caspase3、collagen Ⅰ and collagen Ⅲ compared with DCM rats.3.Perindopril mediated the protein expression of p-Akt and p-FoxO1 in DCMThe protein expression of p-Akt in DCM rats decreased.and FoxO1 protein expression increased compared with control rats(p<0.05).Perindopril treatment increased p-Akt expression and decreased p-FoxO1 expression compared with DCM rats(p<0.05).Conclusion1.Perindopril treatment improves cardiac dysfunction in DCM rats;2.Perindopril normalized cardiac dysfunction in DCM by a Akt-FoxO1 depending pathway.