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

Abstract

Cardiovascular diseases (CVDs) are the major cause of death globally, with more people dying annually from it, rather than from any other cause. It remains one of the biggest burdens on economy despite improvements over last few decades. One of the important cardiac hypertrophic regulatory paradigm involves alterations in gene expression that are mediated by chromatin remodeling. Histone deacetylase (HDAC) is an important key regulator of cardiac hypertrophy and involved in cardiac remodeling and hypertrophic gene regulation. The role of HDAC in heart is varying and has been shown to control events including hypertrophy, fibrosis, contractility, autophagy and energy metabolism. Various data suggest that class I and class II HDACs play opposing roles in the regulation of hypertrophic pathways. Further, experimental studies have revealed that HDAC inhibition suppress and block the progression of cardiac hypertrophy. Valproic acid has been reported to be inhibiting HDAC enzyme. Hence, the aim of present study was to evaluate the effect of magnesium valproate on isoproterenol (ISO) induced cardiac hypertrophy and partial abdominal aorta constriction (PAAC) induced cardiac hypertrophy and determine its mechanism of action. In ISO induced cardiac hypertrophy, isoproterenol (5 mg/kg/day, i.p.) was administered for 10 days in healthy adult Wistar rats of either sex. Control group received normal saline and treated group received magnesium valproate (210 mg/kg/day, p.o.) for 10 days. After 10 days animals were sacrificed and various biochemical and cardiac parameters were analyzed. For PAAC induced cardiac hypertrophy, in healthy adult wistar rats, 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 magnesium valproate (210 mg/kg/day, p.o.) for 30 days. PAAC control group and sham control group received normal saline. After 30th day animals were sacrificed and various biochemical and cardiac parameters were evaluated. Parameters evaluated were hypertrophic parameters like cardiac hypertrophy index, Left Ventricular hypertrophic index, heart weight/ body weight ratio, LV weight/ Right ventricle weight ratio, LV wall thickness, cardiomyocyte diameter, hemodynamic parameters, serum lipid profile, cardiac markers like Creatinine kinase-MB, Lactate dehydrogenase, C reactive protein, Na+K+ATPase levels, pro-oxidant and antioxidant levels. ISO control and PAAC 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 magnesium valproate (210 mg/kg/day, p.o.) significantly reduced CHI, LVHI, HW/BW ratio, LVW/RVW, LV thickness and cardiomyocyte diameter in hypertrophic treated rats. There was significant increase in mean arterial blood pressure and heart rate in ISO control and PAAC control rats. Treatment with magnesium valproate (210 mg/kg/day, p.o.) produced significant decrease in mean arterial blood pressure and heart rate. Moreover, there was significant reduction in rate of pressure development and decay in hypertrophic control rats. Treatment with magnesium valproate (210 mg/kg/day, p.o.) significantly increased rate of pressure development and decay suggesting that magnesium valproate preserves cardiovascular functioning. Moreover, ISO control and PAAC control rats produced significant increase in serum total cholesterol, LDL, VLDL, triglyceride and log Tg/HDL ratio while decrease in HDL levels. Treatment with magnesium valproate (210 mg/kg/day, p.o.) significantly reduced serum total cholesterol, LDL, VLDL, triglyceride and log Tg/HDL ratio and significantly increased HDL levels in hypertrophic treated rats. There was significant increase in serum cardiac markers like Lactate dehydrogenase (LDH) and Creatinine kinase- MB (CK-MB) levels in ISO and PAAC control rats. Treatment with magnesium valproate (210 mg/kg/day, p.o.) significantly reduced serum level of LDH and CK-MB in hypertrophic treated rats. Further, hypertrophic control rats exhibited increase levels of C reactive protein (CRP) and Na+K+ATPase activity. Treatment with magnesium valproate (210 mg/kg/day, p.o.) significantly reduced CRP level and Na+K+ATPase activity in hypertrophic treated rats indicating prevention of cardiac damage. Further, ISO control and PAAC control rats showed increase pro oxidant level i.e. malondialdehyde (MDA) and reduced antioxidant levels such as superoxide dismutase (SOD) and reduced glutathione (GSH) levels of the left ventricle. Treatment with magnesium valproate (210 mg/kg/day, p.o.) significantly reduced MDA levels and increased SOD and GSH levels in left ventricle of hypertrophic treated rats. This suggests that magnesium valproate prevents oxidative stress. Reduction of cardiac hypertrophy with treatment of magnesium valproate (210 mg/kg/day, p.o.) in hypertrophic treated rats was further supported by histopathological studies of left ventricle, which showed marked reduction in fibrosis, increased interstitial space, reduced eosinophilia, reduced extravasated RBCs and decreased apoptosis as compared to ISO control and PAAC control rats. In conclusion, our data suggests that magnesium valproate (210 mg/kg/day, p.o.) produces beneficial effects on cardiac hypertrophy as is evident, specifically from reduction in hypertrophic parameters and preserving of LV systolic and diastolic dysfunction.