Sclerostin Exacerbates Cardiac Remodelling after Myocardial Infarction by Attenuated Wnt/β-Catenin Signaling Pathway

Abstract

Objective: Sclerostin (SOST) showed significant elevation in the serum of patients with pathological cardiac remodelling after myocardial infarction (MI). However, the mechanism of SOST in cardiac remodelling remains largely uncharacterised. Methods & Results: The expression of SOST was significantly elevated in the serum of patients with cardiac remodelling, and in infarcted heart after MI induced in C57BL/6 mice by ligation of left anterior descending branch of the coronary artery. Furthermore, loss and gain function of SOST were used to investigate the role of SOST in post-infarct cardiac remodelling in vivo and in vitro. Overexpressing SOST promoted proliferation and migration of cardiac fibroblasts (CFs) while inhibited angiogenesis of cardiac microvascular endothelial cells (CMECs). In addition, overexpressing SOST in mice was demonstrated significantly deteriorated post-infarct cardiac remodelling, which shown increased LV end systolic and end diastolic dimensions, decreased ejection fraction and fractional shortening, exacerbated inflammatory injury, increased myocyte cross-section area and myocardial fibrosis. However, suppressing SOST showed the opposite results. A mechanism study showed that the expression of Wnt signaling marker proteins was inhibited after overexpressing SOST while promoted after suppressing SOST in vivo and in vitro. Conclusion: In the present study, we demonstrated that SOST exacerbates post-infarct pathological myocardial remodeling by inhibiting angiogenesis of CMECs while promoting the proliferation of CFs, which related to the Wnt signaling pathway. These results suggested that SOST might act as a biomarker to predict detrimental postinfarct cardiac remodelling. Therefore, targeting SOST may hold a new therapeutic potential in treating MI. Funding: This study was funded by National Science Foundation (grant No. 81703877), Featured Innovative Project from Guangdong Provincial Universities (2019KTSCX029), Young Talents Support Project from China Association of Chinese Medicine (2019-QNRC2-C06), Team of prevention and treatment of acute myocardial infarction with Chinese medicine (2019KCXTD009). Declaration of Interest: None to declare. Ethical Approval: The project has been approved by the ethics committee of Guangdong Provincial Hospital of Chinese Medicine (B2015-129-01).