1. Academic Validation
  2. The 5-Lipoxygenase Inhibitor Zileuton Protects Pressure Overload-Induced Cardiac Remodeling via Activating PPAR α

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

  • Oxid Med Cell Longev. 2019 Nov 3;2019:7536803. doi: 10.1155/2019/7536803.
Qing-Qing Wu 1 2 3 Wei Deng 1 2 3 4 Yang Xiao 1 2 3 Jiao-Jiao Chen 1 2 3 Chen Liu 1 2 3 Juan Wang 4 Yankai Guo 5 Mingxia Duan 1 2 3 Zhulan Cai 1 2 3 Saiyang Xie 1 2 3 Yuan Yuan 1 2 3 Qizhu Tang 1 2 3
Affiliations

Affiliations

  • 1 Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China.
  • 2 Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China.
  • 3 Hubei Key Laboratory of Cardiology, Wuhan 430060, China.
  • 4 Department of Cardiology, The Fifth Affiliated Hospital of Xinjiang Medical University, Ürümqi, China.
  • 5 Department of Pacing and Electrophysiological, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830011, China.
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 PPARα, but not PPARγ or PPARθ, thus inducing Keap and NRF2 activation. This was confirmed with the PPARα inhibitor GW7647 and NRF2 siRNA, which abolished the protective effects of zileuton on cardiomyocytes. Moreover, PPARα 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 PPARα/NRF2 signaling.

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