Abstract 4302: Cripto Stimulates Myocardial Proliferation and Enhances Ventricular Function in Ischemic Cardiomyopathy
Ischemic cardiomyopathy is a global health concern with limited highly effective therapy, thus prompting the search for novel molecular and cellular myocardial repair strategies. We have previously reported preliminarily inducing a myocardial proliferative response with Cripto-1 (CR-1), a member of the EGF-CFC protein family that performs an essential role in embryologic cardiac lineage specification and differentiation. CR-1−/− ES cells fail to form beating cardiomyoctyes. CR-1 activates cellular proliferation and survival pathways. We hypothesize that in a heart failure model, local myocardial delivery of CR-1 will induce myocardial proliferation and augment hemodynamic function via activation of the MAPK pathway. Male Wistar rats underwent left anterior descending coronary artery ligation followed by peri-infarct injection of CR-1 or control. Activation of intracellular proliferation pathways was elucidated with ELISA in peri-infarct tissue sampled 30 minutes following ligation. Cellular proliferation was examined by western blot of proliferating cell nuclear antigen (PCNA) in hearts explanted 48 hours after surgery. Borderzone myofilament density was quantified two weeks after surgery. Echocardiography and left ventricular pressure catheter evaluated myocardial function two weeks post-ligation. Table 1⇓ exhibits the effects of CR-1 on the MAPK pathway. MAPK, Phosphohistone H3, and PCNA were elevated in peri-infarct myocardium. Phosphorylated AKT was decreased. The functional benefits of CR-1 are also exhibited. Myofilament density was increased. Echocardiography revealed increased ejection fraction and fractional shortening. Intracavitary pressure catheter demonstrated increased maximal left ventricular pressure and dP/dtmax. CR-1 induces cardiac cellular proliferation and enhances hemodynamic function in ischemic cardiomyopathy via activation of the MAPK pathway.