PMID:11282895

Citation	Yamashita, K, Kajstura, J, Discher, DJ, Wasserlauf, BJ, Bishopric, NH, Anversa, P and Webster, KA (2001) Reperfusion-activated Akt kinase prevents apoptosis in transgenic mouse hearts overexpressing insulin-like growth factor-1. Circ. Res. 88:609-14
Abstract	Abstract -Hearts of wild-type and insulin-like growth factor-1 overexpressing (Igf-1(+/-)) transgenic mice were subjected to Langendorff perfusions and progressive periods of ischemia followed by reperfusion. Apoptosis was measured by DNA nucleosomal cleavage and a hairpin probe labeling assay to detect single-base overhang. Transgenic hearts subjected to 20 minutes of ischemia and 4 hours of reperfusion (I/R) sustained a rate of apoptosis of 1.8+/-0.3% compared with 4.6+/-1.1% for wild-type controls (n=4; P<0.03). Phosphorylation of the protein kinase Akt/protein kinase B was elevated 6.2-fold in transgenic hearts at baseline and increased another 4.4-fold within 10 minutes of reperfusion, remaining elevated for up to 2 hours. I/R activated Akt in wild-type hearts but to a lesser extent (1.6+/-0.3-fold). Pretreatment of transgenic hearts with wortmannin immediately before and during ischemia eliminated reperfusion-mediated activation of Akt and neutralized the resistance to apoptosis. The stress-activated kinase p38 was also activated during ischemia and reperfusion in both wild-type and transgenic hearts. Perfusion with the p38 inhibitor SB203580 (10 micromol/L) blocked both p38 activation and phosphorylation of Akt and differentially modulated apoptosis in wild-type and transgenic hearts. Pretreatment with SB203580 reduced apoptosis in wild-type hearts but increased apoptosis in transgenic hearts. These results demonstrate that Akt phosphorylation during I/R is modulated by IGF-1 and prevents apoptosis in hearts that overexpress the IGF-1 transgene.
Links	PubMed
Keywords	Androstadienes/pharmacology; Animals; Apoptosis/physiology; DNA Fragmentation/drug effects; Enzyme Activation/drug effects; Enzyme Inhibitors/pharmacology; Female; Genotype; Imidazoles/pharmacology; Insulin-Like Growth Factor I/genetics; Insulin-Like Growth Factor I/metabolism; Male; Mice; Mice, Transgenic; Mitogen-Activated Protein Kinases/metabolism; Myocardial Ischemia/physiopathology; Myocardial Reperfusion; Myocardium/metabolism; Myocardium/pathology; Perfusion; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins/metabolism; Proto-Oncogene Proteins c-akt; Pyridines/pharmacology; p38 Mitogen-Activated Protein Kinases
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