Overexpression of Calreticulin Promotes Cardiac Fibroblasts Activation Via Regulating IRE1 Pathway

Abstract Calreticulin (CRT) is an endoplasmic reticulum (ER) chaperone involved in cardiac fibroblasts (CFs) activation. It has been reported that the expression of CRT increased in the process of CFs activation. However, the role of CRT in CFs activation and the mechanism is not yet fully elucidated. Therefore, we aimed to verify whether CRT was involved in CFs activation and the possible mechanism underlying this process. We found that CRT protein level was elevated in AngⅡ-induced CFs activation. Knocking down CRT by its siRNA could decrease the protein expression of connective tissue growth factor (CTGF), α-smooth muscle actin (α-SMA), and transforming growth factor-β (TGF-β), and meanwhile attenuate proliferation and migration ratio of CFs. Moreover, the proliferation and migration rates of CFs were promoted and the expression of CTGF, α-SMA and TGF-β were increased when transfection with high-titer adenovirus of CRT. In AngⅡ-induced CFs, inositol-requiring enzyme 1(IRE-1), one of the main ER pathways, was inhibited through CRT silence and activated through CRT overexpression. Overall, this study demonstrates that CRT overexpression could promote AngⅡ induced-CFs activation by activating IRE1 pathway, which could be a potential target for CFs activation.