Insulin-like growth factor-1 induces Mdm2 and down-regulates p53, attenuating the myocyte renin-angiotensin system and stretch-mediated apoptosis

Insulin-like growth factor (IGF)-1 inhibits apoptosis, but its mechanism is unknown. Myocyte stretching activates p53 and p53-dependent genes,leading to the formation of angiotensin II (Ang II) and apoptosis, Therefore, this in vitro system was used to determine whether IGF-1 interfered with p53 fun ction and the local renin-angiotensin system (RAS), decreasing stretch-indu ced cell death. A single dose of 200 ng/ml IGF-1 at the time of stretching decreased myocyte apoptosis 43% and 61% at 6 and 20 hours. Ang II concentra tion was reduced 52% at 20 hours. Additionally, p53 DNA binding to angioten sinogen (Aogen), AT(1) receptor, and Bar was markedly down-regulated by IGF -1 via the induction of Mdm2 and the formation of Mdm2-p53 complexes. Concu rrently, the quantity of p53, Aogen, renin, AT(1) receptor, and Bar was red uced in stretched myocytes exposed to IGF-1, Conversely, Bcl-2 and the Bcl- 2-to-Bax protein ratio increased. The effects of IGF-1 on cell death, Ang I I synthesis, and Bar protein were the consequence of Mdm2-nduced down-regul ation of p53 function. In conclusion, the anti-apoptotic impact of IGF-1 on stretched myocytes was mediated by its capacity to depress p53 transcripti onal activity, which limited Ang II formation and attenuated the susceptibi lity of myocytes to trigger their endogenous cell death pathway.