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.