Follistatin-like 1 is an Akt-regulated cardioprotective factor that is secreted by the heart

Abstract

Background - The Akt protein kinase is an important mediator of cardiac myocyte growth and survival. To identify factors with novel therapeutic applications in cardiac diseases, we focused on the identification of factors secreted from Aktl-activated cells that have cardioprotective effects through autocrine/paracrine mechanisms. Methods and Results - Using an inducible Aktl transgenic mouse model, we have found that follistatin-like 1 (Fstll) protein and transcript expression are increased 4.0- and 2.0-fold, respectively, by Akt activation in the heart (P<0.05). Fstll transcript was also upregulated in response to myocardial stresses including transverse aortic constriction, ischemia/reperfusion injury, and myocardial infarction. Adenovirus-mediated overexpression of Fstll protected cultured neonatal rat ventricular myocytes from hypoxia/reoxygenation-induced apoptosis (P<0.01), and this protective effect was dependent on the upregulation of both Akt and ERK activities. Conversely, knockdown of Fstll in cardiac myocytes decreased basal Akt signaling and increased the frequency of apoptotic death in vitro (P<0.01). The intravenous administration of an adenoviral encoding Fstll to mice resulted in a 66.0% reduction in myocardial infarct size after ischemia/reperfusion injury that was accompanied by a 70.9% reduction in apoptosis in the heart (P<0.01). Conclusions - These results indicate that Fstll is a cardiac-secreted factor that functions as an antiapoptotic protein. Fstll could play a role in myocardial maintenance and repair in response to harmful stimuli. © 2008 American Heart Association, Inc.