Inhibition of inducible nitric oxide synthase (iNOS) by simvastatin attenuates cardiac hypertrophy in rats

Abstract

Background: The left ventricular hypertrophy (LVH) occurs in response to the haemodynamic overload in some physiological and pathological conditions. This study was designed to investigate the possible cardioprotective effect of simvastatin (SIM) treatment against isoproterenol (ISO)-induced LVH and the probable underlying mechanism in adult male Wistar rats.

Materials and methods: Animals were allocated into four groups. Rats of control group received normal saline orally for 30 days and intraperitoneally for the last 7 days. Rats of SIM group received SIM orally (10 mg/kg/day in saline) for 30 days. Rats of ISO group received normal saline orally for 30 days and ISO intraperitoneally (5 mg/kg) for the last 7 days to induce LVH. Rats of ISO/SIM group received SIM for 30 days and ISO intraperitoneally for the last 7 days. At the end of the experiment, all animals were sacrificed by cervical decapitation under anaesthesia. Truncal blood was collected and serum was separated and used for biochemical assay. The heart was dissected and processed for histological and immunohistochemical studies.

Results: The results of the present study confirmed the ISO-induced myocardial lesions including significant increase of heart weight (HW), heart weight/body weight (HW/BW) ratio, LVH, interstitial myocardial fibrosis (increased collagen types I and III), inflammatory cellular infiltration, necrosis of cardiomyocytes, and increased expression of inducible nitric oxide synthase (iNOS) and thioredoxin in cardiomyocytes. These changes were accompanied by significant increase in serum levels of troponin-T, creatine phosphokinase-MB (CPK-MB), tumour necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). Co-administration of SIM to ISO-injected rats significantly reduced all these cardiac changes and serum biochemical markers in addition to marked depletion of iNOS and thioredoxin expression in cardiomyocytes.

Conclusions: It is concluded that SIM co-administration attenuated ISO-induced cardiac lesions including LVH by inhibiting iNOS expression in cardiomyocytes.

Keywords: collagen; immunohistochemistry; inducible nitric oxide synthase; isoproterenol; left ventricular hypertrophy; rats; simvastatin; thioredoxin.