Knockout of Canopy 2 activates p16INK4a pathway to impair cardiac repair

Background Cardiac repair depends on angiogenesis and cell proliferation. Previously we identified Canopy 2 (CNPY2) as a secreted angiogenic growth factor which promotes neovascularization. We investigated the role of CNPY2 in cardiac repair following myocardial infarction (MI) and the possible mediators involved using Cnpy2 knockout (KO) mice and human cardiac tissue. Methods and results Cardiac tissue from patients with end-stage heart failure had significantly lower endogenous CNPY2 expression compared to samples from control patients. CNPY2 expression in mouse hearts significantly decreased following MI. Significantly less leukocyte and endothelial cell proliferation was found in Cnpy2 KO than wild-type (WT) mice post MI which contributed to impaired angiogenesis, tissue repair, and decreased cardiac function (fractional shortening: WT: 21.1 ± 2.1% vs. KO: 16.4 ± 1.6%, p Conclusions Cardiac injury and progressive heart failure were associated with decreased CNPY2 levels in both humans and mice. Knockout of Cnpy2 resulted in up-regulation of p16INK4a which impaired cardiac function and tissue repair. These data suggest that CNPY2 is an important regulator of p16INK4a and promotes cell proliferation and tissue repair through inhibition of the p16INK4a pathway. CNPY2 treatment may offer a new approach to restore cardiac function after an MI.