Abstract 4362613: Asiatic Acid, A Novel Peroxisome Proliferator-Activated Receptor Alpha Agonist, Ameliorates Cardiac Hypertrophy By Reducing Reactive Oxygen Species Accumulation

Background: Cardiac hypertrophy is a leading cause of morbidity and mortality worldwide. Being a chronic myocardial disease, it comes with a plethora of changes inside the cellular milieu. Metabolic shift, excess fibrosis of tissue, and cell death are a few examples of those changes. Research has shown that excess accumulation and activity of reactive oxygen species (ROS) inside the affected myocardium are one of the early signatures of pathological cardiac hypertrophy. Phytochemicals are naturally occurring compounds that show promising antioxidant prowess in the regression of a wide range of cardiac pathophysiologies. Research Questions: This present study was designed to explore the antihypertrophic potential of Asiatic acid, a natural triterpenoid isolated from Centella asiatica, a plant native to India. The study also focused on cellular signaling pathways that were modulated by the Asiatic acid treatment. Methods: Adult Wistar rats and primary cardiomyocytes were used in this study to test the hypotheses. Pressure overload-induced pathological cardiac hypertrophy was generated by the Renal Artery Ligation (RAL) method in vivo and by Ang-II administration in vitro. Asiatic acid was administered by intraperitoneal injection (I.P.) in vivo. Animals were used in experimentation following ethical clearance by the institutional animal ethics committee and CCSEA, Govt. of India. Echocardiography, PCR, Western blot, and Fluorescence imaging assays were used to study various functional&structural parameters and gene&protein expressions. Results: Asiatic acid treatment resulted in significantly reduced expression of pathological cardiac hypertrophic marker genes as well as improved cardiac function. Asiatic acid treatment also downregulated cellular and mitochondrial reactive oxygen species (ROS) accumulation, leading to the restoration of mitochondrial membrane potential of diseased cardiomyocytes, increased ATP production, and reduced cellular apoptosis. Our analysis revealed that the augmented cellular antioxidant prowess is mediated by Asiatic acid-driven Peroxisome Proliferator-Activated Receptor alpha (PPARalpha) agonism during pathological cardiac hypertrophy. Conclusion: This study is the first to report the antihypertrophic role of Asiatic acid, which acts as a PPARalpha agonist. This study also intricately deciphers the role of PPARalpha in modulating ROS in the context of cardiac pathophysiology.