Activation of Smo/Gli1 pathway attenuates cardiac fibrosis by suppressing G1 / S phase transition and cell proliferation in cardiac fibroblasts in mice

Cardiac fibrosis is the activation of cardiac fibroblasts (CFs) and deposition of extracellular matrix caused by various injurious factors, which affects cardiac function and structure and ultimately leads to the development of heart failure. Studies have shown that the Sonic Hedgehog (Shh) signalling pathway is reactivated after myocardial ischaemia and regulates cardiac tissue repair. However, the effect of Shh signalling pathway on the biological function of CFs and the mechanism of its regulation have not been clarified, so we explored it through a series of in vivo and in vitro experiments. Our results demonstrated that activation of Smoothened (Smo), a key molecule in the Shh signalling pathway, inhibits CFs G1/S phase transition and proliferation. Adenoviral knockdown of Gli1, a downstream transcription factor of the Shh signalling pathway, largely reversed the functional inhibition of CFs caused by activation of Smo, and conversely, overexpression of Gli1 was consistent with Smo activation effects. Further results indicated that the effects of Smo/Gli1 pathway may be mediated by AKT. Additionally, in a cardiac remodelling model, early activation of Smo for intervention was observed to not only improve the extent of fibrosis, but also to have a protective effect on cardiac function and structure. These results suggest that activation of Smo may inhibit the proliferation of CFs and have an antifibrotic effect in vivo. This suggests that the Shh signalling pathway may be a potential therapeutic target for cardiac fibrosis.