Notum Protects Against Myocardial Infarction-Induced Heart Dysfunction By Alleviating Cardiac Fibrosis

Cardiac fibrosis is a pathological reparative process that occurs subsequent to myocardial injury. It is associated with cardiac systolic and diastolic dysfunction and reduced cardiac compliance that eventually leads to heart failure. Delaying or inhibiting the progression of pathological myocardial fibrosis is of great significance for the treatment of many cardiovascular diseases. The Wnt signaling pathway is closely related to the occurrence of organ fibrosis, and Notum is a highly conserved secreted feedback inhibitor of Wnt signaling. It has been shown that Notum acts as a regulator in many organs, such as the aging intestinal epithelium, adult ventricular-subventricular zone neurogenesis, and mouse tooth root development. However, the role and mechanism of Notum on cardiac fibrosis are not well-understood. In this study, we found that Notum significantly increased survival rate and improved cardiac function following myocardial infarction in mice. More importantly, Notum inhibited the Wnt/β-catenin signaling pathway and senescence of cardiac fibroblasts, thereby decreasing the activation of cardiac fibroblasts, reducing the excessive deposition of extracellular matrix, and ultimately inhibiting the occurrence of cardiac fibrosis. Taken together, our findings demonstrated the anti-fibrotic effects of Notum on maladaptive cardiac fibrosis, and suggest that it may be a new strategy for the treatment of cardiac fibrosis.