Osteopontin aggravates myocardial fibrosis by promoting phenotypic transition of cardiac fibroblasts via Hippo-YAP pathway.

Osteopontin (OPN), a glycosylated protein ubiquitously in cellular matrix, exhibits a low expression in normal myocardial tissue but a high expression in fibrotic myocardial tissue. However, the action and mechanisms of OPN on the pathogenesis of myocardial fibrosis (MF) remain unclear. The purpose of the study is to investigate the action and mechanisms of OPN on the occurrence and development of MF, emphasizing abnormal activation of cardiac fibroblasts (CFs) and extracellular matrix (ECM) deposition. Both NIH-3T3 cells and C57BL/6 J mice were infected with OPN over-expression adenoviruses (Ad-Spp1). Cardiac function and fibrosis degree were evaluated in the presence and absence of angiotensin (AngII) (in vitro) or isoprenaline (ISO) (in vivo). Our data demonstrate that OPN over-expression results in myocardial injury and ECM accumulation under the physiological condition. Moreover, it exacerbates such effects under the pathological condition induced by AngII or ISO; in contrast, OPN knockdown attenuates the fibrotic response in vitro induced by AngII. Interestingly, OPN significantly promotes phenotypic conversion of CFs, characterized as elevated levels of α-SMA and Vimentin, with remarkable proliferation and migration in myocardial tissue. Mechanistically, our data indicate that such effects of OPN are mediated by nuclear translocation of YAP/TAZ via Hippo-YAP pathway, dependent of the membrane receptor integrin αVβ3. Overall, OPN plays significant roles in the phenotypic transition of CFs via integrin-Hippo-YAP axis, ultimately leading to MF. The findings highlight the novel mechanisms of OPN triggering MF and would offer an early marker and potential targets for the prevention and treatment of MF.