Overexpression of insulin-like growth factor-1 attenuates the myocyte renin-angiotensin system in transgenic mice

Constitutive overexpression of insulin-like growth factor-1 (IGF-I) in myoc ytes protects them from apoptosis and interferes with myocyte hypertrophy i n the normal and pathological heart. Conversely, angiotensin II (Ang II) tr iggers cell death and promotes myocyte hypertrophy. Moreover, activation of p53 upregulates the cellular renin-angiotensin system (RAS). Therefore, IG F-1 overexpression in FVB.Igf+/- mice may downregulate the local RAS throug h the attenuation of p53 and p53-inducible genes. On this basis, p53 DNA bi nding activity to angiotensinogen (Aogen), bar, and the AT(1) receptor was determined in left ventricular myocytes from FVB.Igf-/- and FVB.Igf+/- mice . The quantity of Bar, Bcl-2, Aogen, and AT(1) receptor in these cells was evaluated. The presence of Mdm2-p53 complexes was also established. Finally , Ang Il levels in myocytes were measured. Upregulation of IGF-I in myocyte s was associated with a protein-to-protein interaction between Mdm2 and p53 , which attenuated p53 transcriptional activity for bar, Aogen, and AT(1) r eceptor. Similarly, the amount of Bar. Aogen, and AT(1) receptor proteins i n these cells decreased. In contrast, the expression of Bcl-2 remained cons tant. The downregulation of Aogen in myocytes from FVB.Igf+/- mice was char acterized by a reduction in Ang Il. In conclusion, IGF-1 negatively influen ces the myocyte RAS through the upregulation of Mdm2 and its binding to p.5 3. This may represent the molecular mechanism responsible for the effects o f IGF-I on cell viability and myocyte hypertrophy in the nonpathological an d pathological heart in vivo.