The 5-Lipoxygenase Inhibitor Zileuton Protects Pressure Overload-Induced Cardiac Remodeling via Activating PPAR<i>α</i>

Abstract

Zileuton has been demonstrated to be an anti-inflammatory agent due to its well-known ability to inhibit 5-lipoxygenase (5-LOX). However, the effects of zileuton on cardiac remodeling are unclear. In this study, the effects of zileuton on pressure overload-induced cardiac remodeling were investigated and the possible mechanisms were examined. Aortic banding was performed on mice to induce a cardiac remodeling model, and the mice were then treated with zileuton 1 week after surgery. We also stimulated neonatal rat cardiomyocytes with phenylephrine (PE) and then treated them with zileuton. Our data indicated that zileuton protected mice from pressure overload-induced cardiac hypertrophy, fibrosis, and oxidative stress. Zileuton also attenuated PE-induced cardiomyocyte hypertrophy in a time- and dose-dependent manner. Mechanistically, we found that zileuton activated PPAR<i>α</i>, but not PPAR<i>γ</i> or PPAR<i>θ</i>, thus inducing Keap and NRF2 activation. This was confirmed with the PPAR<i>α</i> inhibitor GW7647 and NRF2 siRNA, which abolished the protective effects of zileuton on cardiomyocytes. Moreover, PPAR<i>α</i> knockdown abolished the anticardiac remodeling effects of zileuton in vivo. Taken together, our data indicate that zileuton protects against pressure overload-induced cardiac remodeling by activating PPAR<i>α</i>/NRF2 signaling.