Suppression of SMOC2 alleviates myocardial fibrosis via the ILK/p38 pathway

Fibrosis of the myocardium is one of the main pathological changes of adverse cardiac remodeling, which is associated with unsatisfactory outcomes in patients with heart disease. Further investigations into the precise molecular mechanisms of cardiac fibrosis are urgently required to seek alternative therapeutic strategies for individuals suffering from heart failure. SMOC2 has been shown to be essential to exert key pathophysiological roles in various physiological processes in vivo, possibly contributing to the pathogenesis of fibrosis. A study investigating the relationship between SMOC2 and myocardial fibrosis has yet to be conducted.

Mice received a continuous ISO injection subcutaneously to induce cardiac fibrosis, and down-regulation of SMOC2 was achieved by adeno-associated virus-9 (AAV9)-mediated shRNA knockdown. Neonatal fibroblasts were separated and cultured in vitro with TGFβ to trigger fibrosis and infected with either sh-SMOC2 or sh-RNA as a control. The role and mechanisms of SMOC2 in myocardial fibrosis were further examined and analyzed.

SMOC2 knockdown partially reversed cardiac functional impairment and cardiac fibrosis in vivo after 21 consecutive days of ISO injection. We further demonstrated that targeting SMOC2 expression effectively slowed down the trans-differentiation and collagen deposition of cardiac fibroblasts stimulated by TGFβ. Mechanistically, targeting SMOC2 expression inhibited the induction of ILK and p38 in vivo and in vitro, and ILK overexpression increased p38 phosphorylation activity and compromised the protective effects of sh-SMOC2-mediated cardiac fibrosis.

Therapeutic SMOC2 silencing alleviated cardiac fibrosis through inhibition of the ILK/p38 signaling, providing a preventative and control strategy for cardiac remodeling management in clinical practice.