INTRODUCTION
Cardiac fibroblasts (CFs) are abundant in adult mammalian heart and are involved not only play a pivotal role in maintaining structural integrity and function, but also in cardiac remodeling in connection with myocardial injury or pathologies [1]. More and more studies have shown that CFs secrets both pro- and anti-inflammatory cytokines are involved in cardiac inflammation [2]. As pro-inflammatory cytokine, IL-1β, IL-6 and TNF-α, which can regulate differentiation of CFs to myofibroblasts [3-4] and the secretion of various MMPs and of TIMP-1, as well as promoting extracellular matrix (ECM) deposition [5]. And yet, IL-10 can reduce the fibrosis by inhibiting the proliferation of rat CFs [6]. Accordingly, CFs may be regarded as an important cell and molecular target for inhibition of myocardial fibrosis, but the inflammatory mechanisms have bot been fully elucidated yet.
Many studies have shown that NF-κB signaling pathway is participated in the release of inflammatory factors in CFs via NF-κB activation. Recently, PPARs has been shown to have anti-inflammatory and anti-proliferative properties.[7]. Interestingly, PPAR-γ ligand has been shown to abate cardiac fibrosis in various in situ models of cardiac hypertrophy and failure [8]. More critically, PPAR-γ agonists can effectively inhibit the differentiation of human lung and dermal fibroblasts into myofibroblasts [9]. Activation of PPAR-γ can inhibit the secretion of inflammatory cytokines after LPS treatment [7]. To sum up, these researches put forward the possibility that anti-fibrotic effects of PPARs in the heart are mediated by inhibiting the proliferation and differentiation of CFs.
Up to the present, there is no effective measures to alleviate cardiac fibrosis. Over the years, great attention has been paid to the treatment of myocardial fibrosis. Serelaxin, a recombinant form of human relaxin-2, is considered to be a promising drug for the treatment of acute heart failure (AHF)[10]. Many studies have shown that
serelaxin can markedly decreased renal interstitial fibrosis, lung fibrosis [11] and cardiac fibrosis [12]. Furthermore, serelaxin has been reported to improve the inflammatory response in LPS-induced fibrosis[13]. Study showed that another signaling pathway activated by relaxin, involving peroxisome proliferator-activated receptor gamma (PPAR-γ)[14]. However, PPAR-γ also has anti-inflammatory and antifibrotic effects in several tissues [13]. Although the above-mentioned experimental and clinical data suggests various serelaxin effects on the heart, whether serelaxin alleviates cardiac fibrosis by inhibiting inflammatory effects and its detailed mechanisms have not been explored. This led us to examine whether PPAR-γ was involved in the cellular effects of serelaxin. Thus, special attention was given to the study observing the anti-inflammatory effects of serelaxin on LPS-stimulated CFs and the potential anti-inflammatory mechanism.