Abstract 1059: Identification of the Anti-Apoptosis Activity of Nerve Growth Factor on Cardiac Myocytes.
Neurotrophins (NTs) control the survival and regeneration of neurons. Recent research showed that NTs posses cardiovascular actions. In this study, we investigated the hypothesis that the NT nerve growth factor (NGF) prevents cardiomyocyte apoptosis. We demonstrated that cultured rat neonatal cardiomyocytes (RNCMs) produce NGF and express its trkA receptor. RNCMs given a neutralizing antibody for NGF or the trkA inhibitor K252a underwent apoptosis, thus suggesting that NGF is an endogenous pro-survival factor for cardiomyocytes. Recombinant NGF induced trkA phosphorylation, followed by Ser473-phosphorylation and nuclear translocation of Akt in RNCMs. In response to Akt activation, Forkhead transcription factors Foxo-3a and Foxo-1 were phosphorylated and excluded from the nucleus. Adenovirus (Ad)-mediated NGF over-expression RNCMs protected RNCMs apoptosis induced by either hypoxia/reoxygenation or angiotensin II. Inhibitory approaches using K252a, LY294002 (a pan-phosphatidyl inositol 3-kinase -PI3K- inhibitor), and adenoviruses carrying a dominant negative mutant form of Akt (Ad.DN.Akt) or an Akt-resistant Foxo-3a (Ad.AAA-Foxo-3a) demonstrated that the pathway encompassing trkA, PI3K-Akt, and Foxo is essential for the pro-survival effect of NGF. The anti-apoptosis action of NGF was confirmed in adult myocytes extracted from the mouse heart, which were submitted to the angiotensin II apoptosis test in the presence of recombinant NGF. Finally, intra-myocardial NGF gene transfer prevented cardiomyocyte apoptosis in a murine model of myocardial infarction.