4-OCTYL ITACONATE ATTENUATES ISOPROTERENOL INDUCED MYOCARDIAL DAMAGE VIA NLRP3 INFLAMMASOME PATHWAY, NRF-2/HO-1 AND MAPK PATHWAY IN AN EXPERIMENTAL MODEL

Abstract

Objective: Myocardial infarction (MI) is the major cause of morbidity and mortality worldwide. According to the World Health Organisation, more than 9 million deaths occurred due to ischemic heart disease worldwide in 2016. 4-octyl itaconate (4-OI) is a cell permeable derivative of itaconate with potent anti-oxidative, anti-inflammatory and anti-fibrotic properties. Studies have shown that 4-OI inhibits pro-inflammatory cytokines (IL6, IL1beta, TNF alpha) and activates the anti-oxidant Nrf-2/HO-1 pathway. The aim of the study was to investigate the cardio-protective effect of 4-OI in experimental model of Isoproterenol induced myocardial damage. Design and method: Adult male albino wistar rats were used in the study. They were randomly divided to five groups i.e., normal control group, isoproterenol control group, 4-OI group (2.5, 5 or 10 mg/kg) for 14 days and 4-OI perse group. On the 15th day, rats were anaesthetized and right coronary artery was cannulated to record hemodynamic parameters. Following this, blood was withdrawn using cardiac puncture, heart was excised and preserved for analysis of biochemical, histopathological and molecular pathway studies. Results: Isoproterenol administration to rats resulted in induction of Myocardial damage as shown by impairment in hemodynamic parameters, left ventricular dysfunction and raised cardiac injury markers. Treatment with 4-OI significantly improved hemodynamic and cardiac injury markers (CKMB, LDH). Further, 4OI significantly reduced oxidative stress (enhanced levels of SOD, GSH, decreased MDA levels) and inflammation (reduced levels of TNF alpha, IL-6, IL-1beta and NLRP3). Further it activated the Nrf-2-HO-1 pathway while inhibits the inflammatory NFKB pathway. Apart from this, it also ameliorated apoptosis by decreasing the expression of Bax, caspase-3 and increasing the expression of anti-apoptotic Bcl-2. It also inhibited inflammatory MAPK proteins (JNK, phospho JNK, P38, phospho P38) while enhancing the expression of pro-survival kinases ERK1/2, and Phospho ERK1/ 2. Conclusions: Oral administration of 4-OI at a dose of 10 mg/kg ameliorated the severity of isoprotorenol-induced cardio-toxicity in rats via NLRP-3 inflammasome pathway, MAPK and Nrf-2/HO1 pathway and by maintaining morphological structure of heart tissue and oxidative stress profile along with reduced inflammation and apoptosis.