The Effects Of Simvastatin On Cardiac Hypertrophy And Its Mechanisms

Objective: To investigate the effect of SIM on cardiac hypertrophy in vivo and vitro and related mechanisms.Methods: Neonatal rat cardiac hypertrophy was induced by Angâ…¡or CT-1,rat model of ventricular hypertrophy was established by banding abdominal aorta.Total protein content was measured by Lowary's method and the cell surface area was measured by phase contrast microscope and image analysis system(HJ2000).The localization of p-STAT3 in left ventricle in cultured cardiomyocytes was determined by immunocytochemistry. The gene expression of AGT mRNA and c-fos mRNA were detected by RT-PCR.Heart systolic blood pressure,hert weight/body weight (HW/BW) and left ventricle weight/body weight(LVW/BW) were measured. The morphous of cardiac myocytes were observed by HE staining. The expression of p-JAK2 and p-STAT3 were detected by western blot.Results:1. The total protein content and cell surface area of cardiomyocytes increased significantly after Angâ…¡treatment,SIM inhibited these effects of Angâ…¡, which was similar with captopril.2. CT-1 could dose dependently increase the total protein content of cardiomyocytes while SIM could inhibit the effect of CT-1 on cardiomyocytes.3. CT-1 significantly activated the expression of p-JAK2 and p-STAT3, p-JAK2 and p-STAT3 activation was inhibited by SIM or Janus Kinase-selective inhibitor AG490, and the expression of p-JAK2 and p-STAT3 showed no change by the pretreatment of SIM or AG490. p-STAT3 localized in both cytoplasm and nucleus uniformly in cardiomyocytes by the pretreatment of CT-1. SIM or AG490 could inhibit the effect of CT-1.4. CT-1 significantly enhanded the gene expression of AGT mRNA and c-fos mRNA, which was inhibited by the pretreatment of AG490 or SIM.5. The heart systolic blood pressure,hert weight/body weight (HW/BW) and left ventricle weight/body weight(LVW/BW) and the cross sectional area of cardiomyocytes increased in abdominal aorta constricted induced cardiac hypertrophic rats, these effects could be inhibited by the pretreatment of SIM or Cap in abdominal aorta banding induced cardiac hypertrophic rats.6. Banding the abdominal aorta of rats could significantly activate p-JAK2 and p-STAT3 , p-JAK2 and p-STAT3 activation was inhibited by SIM or Cap.Conclusions:1. Angâ…¡can induce cultural rat cardiomyocyte hypertrophy; CT-1 can induce cardiomyocyte hypertrophy, the mechanism may be related to JAK/STAT signal pathway, mediated by which AGT is up-regulated , and Angâ…¡is more inverted, thus a cascade reaction of cardiomyocyte hypertrophy is formed.2. SIM can inhibit Angâ…¡-induced cardiomyocyte hypertrophy; SIM can inhibit CT-1-induced cardiomyocyte hypertrophy, the mechanism may be related to the inhibition of JAK/STAT signal pathway and the activation of down-expression of AGT mRNA,c-fos mRNA.3. Constrction of abdominal aorta can induce cardiac hypertrophy in rats, SIM can inhibit abdominal aorta banding induced cardiac hypertrophy, the mechanism is related to the inhibition of JAK/STAT signal pathway.