Co-Chaperone-Mediated Suppression of LPS-Induced Cardiac Toxicity Through NFκB Signaling.

Co-chaperone cytoplasmic constitutive active/androstane receptor retention protein (CCRP), a member of heat shock protein (HSP) 40, was first characterized to retain a nuclear-destined protein in the cytoplasm. Here we have used CCRP KO mice and demonstrated that CCRP suppresses lipopolysaccharide (LPS)-induced cardiac toxicity in mice. LPS treatment decreased heart rates in CCRP KO mice, but not in wild-type (WT) mice. In addition, LPS-treated KO mice showed reduced fraction shortening, an indicator of ventricular contractile function, to a greater degree than WT mice did. Rat cardiomyocyte-derived H9c2 cells, in which CCRP is not expressed, were used to examine a cell signal through which CCRP suppressed LPS-induced cardiac toxicity. Overexpression of CCRP prevented p65, a nuclear factor κB (NFκB) subunit, from accumulating in the nucleus after LPS treatment. As observed with H9c2 cells, nuclear accumulation of p65 was found to be higher in the hearts of KO mice than WT mice after LPS treatment. Furthermore, induction of TNFα by LPS was markedly suppressed by CCRP in H9c2 cells as well as in LPS-treated mouse serum. In supporting the notion that CCRP repressed the LPS-induced NFκB signaling, pretreatment with pyrrolidinedithiocarbamate, an NFκB signaling inhibitor, or anti-TNF-α antibody before LPS treatment restored heart rates decreased in KO mice after LPS treatment in a dose-dependent manner. Our present study characterized a novel physiological role of CCRP in protecting cardiac functions through the inhibition of NFκB signaling.