Imine stilbene analog ameliorate isoproterenol-induced cardiac hypertrophy and hydrogen peroxide-induced apoptosis

Abstract

Cardiac hypertrophy is an adaptive response to stress, in order to maintain proper cardiac function. However, sustained stress leads to pathological hypertrophy accompanied by maladaptive responses and ultimately heart failure. At the cellular level, cardiomyocyte hypertrophy is characterized by an increase in myocyte size, reactivation of the fetal gene markers, disassembly of the sarcomere and transcriptional remodelling which are regulated by heart-specific transcription factors like MEF2, GATA4 and immediate early genes like c-jun and c-fos.2. It has been explored and established that the hypertrophic process is associated by oxidative stress and mediated by pathways involving several terminal stress kinases like P38, JNK and ERK1/2. Stilbenoids are bioactive polyphenols and earlier studies have shown that imine stilbene exert cardioprotective and anti aging effects by acting as modulators of Sirt1. The present study was aimed at designing and synthesizing a series of imine stilbene analogs and investigate its anti hypertrophic effects and regulatory mechanism in cardiac hypertrophy and apoptosis. Interestingly one of the analog, compound 3e (10 μM) alleviated isoproterenol (ISO, 25 μM) induced hypertrophy in rat cardiomyocyte (H9c2) cells by showing a marked decrease in the myocyte size. Further, compound 3e also restored the cardiac function by activating the metabolic stress sensor, AMPK. Moreover, molecular docking studies showed stable binding between compound 3e and GSK3β suggesting that compound 3e may directly regulate GSK3β activity and ameliorate ISO-induced cardiac hypertrophy. In agreement with this, compound 3e also modulated the crosstalk of all the hypertrophy inducing terminal Kinases by bringing down the expression to near control conditions. The compound also relieved H₂O₂ (100 μM) mediated ROS and normalized abnormal mitochondrial oxygen demand in hypertrophic conditions indicating the possibility of the compound to show promise in playing a role in cardiac hypertrophy.

Keywords: Apoptosis; GSK3β; Hypertrophy signaling; Imine stilbene analogs (3e); Isoproterenol; MAPK; Molecular docking; Reactive oxygen species; Resveratrol; p38.