Abstract:

Objective To investigate the role and mechanism of collagen triple helical repeat 1（CTHRC1） regulating epidermal growth factor receptor（EGFR）signaling pathway in the formation of hypertensive myocardial remodeling. Methods SD rats were randomLy divided into the following three groups：wild⁃type control（WTC） group，AngⅡ + Stuffer group and AngⅡ + CTHRC1 group，10 rats in each group. Rats in the AngⅡ + Stuffer group and the AngⅡ + CTHRC1 group were pretreated by injecting Stuffer or CTHRC1 through the tail vein at a dose of 1 × 1011 v.g. respectively；after injection for 4 weeks，the rats were received AngⅡ［1.5 mg/（kg·d）］with an osmotic minipump for another 4 weeks. Cardiac function was measured non⁃invasively by transthoracic echocar⁃ diography，and the cardiac fibrosis was assessed by Masson′s trichrome staining. Cardiac fibroblasts（CF）were isolated from the hearts of 2⁃ to 3⁃day⁃old SD rats and divided into：Con group，Ang Ⅱ group，AngⅡ+ sh⁃NC group， AngⅡ+ sh⁃CTHRC1 group and Ang Ⅱ group +sh⁃CTHRC1+Colivelin TFA group. Cell proliferation and migration were assessed by CCK8 assay and wound healing assay，reactive oxygen species（ROS）levels were detected by dihydroethidium fluorescence staining，and the expression of CTHRC1 protein and EGFR/Stat3 signaling pathway was analyzed by western blotting. Results Compared with the WTC group，the cardiac tissue fibrosis of the hyper⁃ tensive rats in the AngⅡ+ stuffer group significantly increased（P < 0.05）. CTHRC1 administration further aggra⁃ vated these pathological changes in hypertensive rats（P < 0.05）. Echocardiography showed that the left ventricularejection fraction decreased and the fractional shortening in the AngⅡ+ CTHRC1 group was greater than that in the AngⅡ+ stuffer group（P < 0.05）. Compared with the control group，the proliferation of CF and the expression of EGFR and Stat3 in the Ang Ⅱ group significantly increased（P < 0.05）. CF migration，ROS levels and fibrosis⁃ related signal（COL1A1，COL3A1，TGF ⁃ β）gene expression in Ang Ⅱ group significantly increased compared with those in the control group（P < 0.05）；sh⁃CTHRC1 pretreatment significantly reversed these changes induced by AngⅡ（P < 0.05）. Furthermore，Colivelin TFA addition largely reduced the beneficial effect of sh ⁃CTHRC1 pretreatment on Ang Ⅱ induction（P < 0.05）. Conclusion CTHRC1 overexpression leads to increased cardiac fibrosis，structural damage and dysfunction in hypertensive rats，and its mechanism of action is related to oxidative stress mediated by activation of the EGFR/Stat3 signaling pathway.

Key words:

collagen triple helical repeat 1, hypertension, myocardial remodeling, EGFR signaling pathway