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PMID:10205143

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Citation

Leri, A, Liu, Y, Wang, X, Kajstura, J, Malhotra, A, Meggs, LG and Anversa, P (1999) Overexpression of insulin-like growth factor-1 attenuates the myocyte renin-angiotensin system in transgenic mice. Circ. Res. 84:752-62

Abstract

Constitutive overexpression of insulin-like growth factor-1 (IGF-1) in myocytes protects them from apoptosis and interferes with myocyte hypertrophy in the normal and pathological heart. Conversely, angiotensin II (Ang II) triggers cell death and promotes myocyte hypertrophy. Moreover, activation of p53 upregulates the cellular renin-angiotensin system (RAS). Therefore, IGF-1 overexpression in FVB.Igf+/- mice may downregulate the local RAS through the attenuation of p53 and p53-inducible genes. On this basis, p53 DNA binding activity to angiotensinogen (Aogen), bax, and the AT1 receptor was determined in left ventricular myocytes from FVB.Igf-/- and FVB.Igf+/- mice. The quantity of Bax, Bcl-2, Aogen, and AT1 receptor in these cells was evaluated. The presence of Mdm2-p53 complexes was also established. Finally, Ang II levels in myocytes were measured. Upregulation of IGF-1 in myocytes was associated with a protein-to-protein interaction between Mdm2 and p53, which attenuated p53 transcriptional activity for bax, Aogen, and AT1 receptor. Similarly, the amount of Bax, Aogen, and AT1 receptor proteins in these cells decreased. In contrast, the expression of Bcl-2 remained constant. The downregulation of Aogen in myocytes from FVB.Igf+/- mice was characterized by a reduction in Ang II. In conclusion, IGF-1 negatively influences the myocyte RAS through the upregulation of Mdm2 and its binding to p53. This may represent the molecular mechanism responsible for the effects of IGF-1 on cell viability and myocyte hypertrophy in the nonpathological and pathological heart in vivo.

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PubMed

Keywords

Angiotensin II/analysis; Angiotensin II/metabolism; Animals; DNA, Complementary; Fluorescent Antibody Technique; Gene Expression/physiology; Humans; Insulin-Like Growth Factor I/genetics; Insulin-Like Growth Factor I/metabolism; Male; Mice; Mice, Transgenic; Muscle Fibers, Skeletal/physiology; Myocardium/chemistry; Myocardium/cytology; Myocardium/metabolism; Myosins/genetics; Precipitin Tests; Promoter Regions, Genetic/physiology; Protein Binding/physiology; Proto-Oncogene Proteins/analysis; Proto-Oncogene Proteins c-bcl-2/analysis; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin/analysis; Renin-Angiotensin System/genetics; Tumor Suppressor Protein p53/metabolism; bcl-2-Associated X Protein

Significance

Annotations

Gene product Qualifier GO ID GO term name Evidence Code with/from Aspect Notes Status


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