Effects Of Valproic Acid Sodium On Cardiac Hypertrophy Induced By Pressure Overload In Rats

Background:Cardiac hypertrophy is an adaptive response to various overloads that leads to a maladaptive state on cardiac function when the stress is prolonged, advanced cardiac hypertrophy itself is associated with an increased risk of morbidity and mortality. So it is necessary to prevent cardiac hypertrophy. Histone deacetylase inhibitors have been shown to inhibit cardiac hypertrophy in vitro and in vivo. Thus, HDAC inhibitors hold promise as potential therapeutic agents in hypertrophy-related heart diseases.Objective:The purpose of this study is to investigate the effect of different doses of valproic acid sodium on the myocardial hypertrophy caused by pressure overload and to find out the possible mechanisms.Methods:1. Grouping40male SD rats were randomly divided into4groups:(1) sham operation group,(2) myocardial hypertrophy group,(3) low dose valproic acid sodium treatment group (200mg/kg-d),(4) high dose valproic acid sodium treatment group (400mg/kg-d)(n=10).2. Model preparationSham group:the abdominal aortal was isolated without being ligated. Myocardial hypertrophy group:pressure overload was achieved by classical surgical constricting the abdominal aortal. After4weeks of surgery, the rats which’s blood pressure more than150mmHg can be used to the experiment. Low dose valproic acid sodium treatment group:valproic acid sodium200mg/kg-d by peritoneal injection. High dose valproic acid sodium treatment group:gave valproic acid sodium400mg/kg-d.(4weeks).3. Indicators for monitoringThe general conditions of all rats were observed carefully, and systolic blood pressure was measured using the tail-cuff method throughout the experiment. All rats were sacrificed8weeks after the operation then the heart weight, left ventricular weight and body weight were measured and the ratio of heart weight to body and left ventricular weight to body were calculated. Then acquired the myocardial samples, using hematoxylin and eosin stain to detect the pathobiological changes of the hearts, using immunohistochemical method to detect the expression of TNF-a, using RT-PCR to detect β-MHC and TNF-a gene’s expression of myocardium.Results:After4weeks of surgery, compared with preoperative and sham group, the blood pressure increased significantly(P<0.05) in myocardial hypertrophy group. After8weeks of surgery, compared with sham group, the blood pressure increased significantly in myocardial hypertrophy group(P<0.05), the heart weight, left ventricular weight, the ratio of heart weight to body weight and the ratio of left ventricular weight to body weight increased significantly(P<0.05); the expression of TNF-α protein increased significantly(P<0.05); β-MHC and TNF-α mRNA’s expression increased significantly (p<0.05). Compared with myocardial hypertrophy group, all of these indexes decreased significantly(P<0.05) in valproic acid sodium treatment group(low and high dose). Compared with low dose valproic acid sodium treatment group, the blood pressure, the heart weight, left ventricular weight, the ratio of heart weight to body weight and the ratio of left ventricular weight to body weight had no significant difference(P>0.05) in high dose group; the expression of TNF-α protein, β-MHC and TNF-α mRNA decreased significantly(P<0.05).Conclusion:1. Valproic acid sodium can prevent the cardiac hypertrophy caused by pressure overload.2. Valproic acid sodium attenuated the expression of pro-inflammatory cytokine in the development of cardiac hypertrophy, demonstrating that valproic acid sodium reduces cardiac hypertrophy, possibly in part through modulation of pro-inflammatory cytokine expression; and the actions of high dose group is more significant.