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.
Highlights
Cardiac remodeling refers to changes in the shape, structure, and function of the heart caused by pathophysiological stimuli [1]
We explored whether zileuton could protect against cardiac remodeling upon pressure overload and the underlying mechanism involved in cardiomyocyte signaling under pathological conditions
The decreased expression levels of the downstream targets keap1 and PGC1α and the nuclear translocation of nuclear respiratory factor 2 (NRF2) in mouse hearts induced by AB surgery were increased by zileuton treatment (Figures 6(a)–6(d)). These phenomena were confirmed in an in vitro study where we found that PE reduced the expression of PPARα and the downstream targets keap1, PGC1α, and NRF2; PE reduced the nuclear translocation of NRF2 in cardiomyocytes, while zileuton treatment blunted these changes (Figures 6(e) and 6(f))
Summary
Cardiac remodeling refers to changes in the shape, structure, and function of the heart caused by pathophysiological stimuli [1]. The signaling involved in cardiac remodeling includes mitogen-activated protein kinase (MAPK), AKT (serine/threonine kinase), Ca2+-calcineurin, and peroxisome proliferator-activated receptors (PPARs) [1, 3]. Among these signaling molecules, PPARs are of great importance. Three PPAR isoforms have been found, PPARα, PPARβ/δ, and PPARγ and they are encoded by separate genes [4]. All of these isoforms participate in the transcriptional regulation of multiple processes and are essential in the pathogenesis of cardiovascular diseases [4]. Targeting PPAR molecules may be a promising therapeutic method for treating HF
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