Investigation into the Effect of Silymarin in Cardiac Hypertrophy and Its Related Mechanism

Abstract

In last few decades, there is ascendancy of cardio vascular diseases as major contributors to total worldwide deaths, representing 30% of all global deaths. There are more people dying from cardiovascular disease than other diseases and the expenditure reaches up to $149 billion annually which accounts the biggest economy burden worldwide. Mitogen activated protein kinase is an important key regulator of cardiac hypertrophy and plays an important role in cardiac remodeling and hypertrophic gene regulation. Amongst the three MAPKs, namely Extra regulated kinase (ERK), c- JUN N- Terminal kinase ( JNK) and p38 kinase, p38 is the key regulator of cardiac hypertrophy which is further divided in 4 isoforms. p38 β is the key regulator of pressure overload cardiac hypertrophy which further leads to activation of many transcription factors like ATF-2, ELK-1, CREB, and MEF-2C. Further, studies reveal that inhibition of MAPK p38 β suppresses and blocks the progression of cardiac hypertrophy. Silymarin has been reported to be inhibiting MAP Kinase. Hence, the aim of present study was to evaluate the effect of silymarin on partial abdominal aortic constriction (PAAC) induced cardiac hypertrophy and determine its mechanism of action. Material and method Healthy adult wistar rats of either sex were used for the study. Cardiac hypertrophy was induced by partial abdominal aortic constriction (PAAC). The abdominal aorta was ligated by 4-0 silk thread along with 7.0 mm diameter blunt needle. The needle was then removed to leave aorta partially constricted and they received silymarin in three different doses 25 mg/kg/day, p.o., 50 mg/kg/day, p.o. and 100 mg/kg/day, p.o. for 9 weeks. PAAC control group and Sham control group received normal saline. After 9 weeks animal were sacrificed and various biochemical and cardiac parameters were evaluated.Results Hypertrophic parameters PAAC induced hypertrophic control rats exhibited significant increase in cardiac hypertrophy index (CHI), Left ventricular (LV) hypertrophic index (LVHI), heart weight to body weight ratio (HW/BW), left ventricular weight to right ventricular weight ratio (LVW/RVW), LV thickness and cardiomyocyte diameter. Treatment with silymarin in dose of 25 mg/kg did not showed significant reduction in LVHI, LV collagen level and cardiomyocyte diameter in hypertrophic treated rats but silymarin in dose of 25 mg/kg significantly reduced the CHI, LVW/RVW ratio, HW/BW ratio, and left ventricle thickness in cardiac hypertrophic treated rats as compared to hypertrophic control rats. Furthermore, silymarin in the dose of 50mg/kg and 100 mg/kg showed significant reduction in CHI, LVHI, HW/BW ratio, LVW/RVW ratio, LV thickness and cardiomyocyte diameter suggesting that silymarin controls cardiac hypertrophy. Hemodynamic parameters There was significant increase in mean arterial blood pressure (MABP), heart rate (HR), QT interval and significant decrease in rate of pressure development and rate of pressure decay in PAAC control rats. Treatment with silymarin in the dose of 25 mg/kg did not produce any reduction in mean arterial blood pressure, heart rate and QT interval but significantly increase in rate of pressure development and decay compared to control rats. Furthermore, silymarin in the dose of 50 mg/kg and 100 mg/kg showed significance decrease in MABP, HR, QT interval and showed significant increase in rate of pressure development and rate of pressure decay compared to hypertrophic control rats, suggesting that silymarin preserves cardiovascular functioning. Lipid profile PAAC control rats exhibited significant increase in serum total cholesterol, LDL, VLDL, triglyceride and log Tg/HDL ratio while decrease in HDL levels. Treatment with silymarin in the dose of 25 mg/kg did not produced significant reduction in serum VLDL, triglyceride, HDL and Tg/HDL ratio and did not increase HDL level but showed a significant reduction in cholesterol and LDL levels.