E3 ligase CHIP restoration facilitates the effect of α1-adrenoceptor blockage on alleviating lipopolysaccharide-caused cardiac fibrosis via downregulating TGF-BR1 expression and Smad2/3 activation

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Abstract Myocardial fibrosis is a serious complication in sepsis and leads to cardiac dysfunction. The carboxy terminus of Hsc70-interacting protein (CHIP), a U-box E3 ligase, defends against sepsis-caused cardiac injury. Here, we explored a novel therapeutic effect of α 1 -adrenoceptor (α 1 -AR) blockage on lipopolysaccharide (LPS)-induced myocardial fibrosis and clarified that its molecular mechanism was related to the restoration of CHIP expression. The results showed that LPS increased the release of norepinephrine (NE) in the myocardium and promoted myocardial fibrosis. NE promoted the cardiac fibroblasts (CFs) differentiation characterized by increased α-SMA and collagen I/III. Blockage of α 1 -AR by prazosin apparently alleviated LPS-induced cardiac fibrosis and NE-caused CFs differentiation. Prazosin decreased phosphorylation of protein kinase C (PKC), p38 and Smad2/3, and reduced nuclear c-Jun level, as well as increased CHIP expression in the NE-stimulated CFs and the myocardium in LPS-treated mice. In vitro and in vivo data suggested that the overexpression of CHIP restrained α-SMA and collagen I/III production, and downregulated TGF-β receptor 1 (TGF-BR1) expression and Smad2/3 phosphorylation induced by NE or LPS respectively. Conversely, the knockdown of CHIP weakened the effect of prazosin. Furthermore, we innovatively revealed that α 1A -AR is the dominant α 1 -AR subtype in CFs, and its specific antagonist, silodosin, eliminated NE-mediated CFs differentiation and LPS-induced myocardial fibrosis, which was consistent with the action of prazosin. These findings demonstrate the protective effect of α 1 -AR blockage against LPS-mediated myocardial fibrosis, which is achieved by directly inhibiting the PKC-p38-Smad2/3 signaling pathway and promoting TGF-BR1 downregulation through restoring CHIP expression.

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