Meox1 Promotes Cardiac Fibrosis and Pathological Remodeling following Myocardial Infarction through Cthrc1/p-Smad2/3 Signaling.

Aims: Myocardial infarction (MI) induces pathological cardiac fibrosis and ventricular remodeling, which leads to cardiac dysfunction and heart failure. Mesenchyme homeobox 1 (Meox1) was shown to be an essential transcriptional switch in fibroblasts activation; however, whether Meox1 is involved in the fibrosis process following MI remains unknown. We aimed to explore the role of Meox1 in cardiac fibrosis and remodeling post-MI and its underlying mechanisms. Methods and results: Herein, we identified that Meox1 was highly expressed in activated fibroblasts (myofibroblasts, Myofbs), in response to MI in mice or transforming growth factor beta 1 (TGF-β1) stimulation in primary cardiac fibroblasts (CFs). Knockdown of Meox1 in Myofbs remarkably attenuated cardiac fibrosis and adverse remodeling post-MI and improved cardiac function. In vitro, Meox1 silencing inhibited the activation, proliferation, migration and fibrotic gene expression of primary CFs, whereas Meox1 overexpression resulted in the opposite biological effects. Mechanistically, Meox1 transcriptionally activated collagen triple helix repeat containing 1 (Cthrc1), which further promoted downstream Smad2/3 phosphorylation, thereby leading to CFs-to-Myofbs conversion. Overexpression of Cthrc1 abolished the cardioprotective effects of Meox1 silencing in mice. Moreover, Cthrc1 knockdown in primary CFs suppressed the effects of Meox1 on facilitating the phosphorylation of Smad2/3 and profibrotic phenotypes. Conclusions: Our study revealed the key regulatory role of Meox1 in promoting cardiac fibrosis and heart failure by inducing the transformation of CFs-to-Myofbs through activating Cthrc1/p-Smad2/3 post-MI. Therefore, Meox1/Cthrc1/p-Smad2/3 signaling pathway might be a promising therapeutic target for cardiac fibrosis and remodeling in MI patients.