Reperfusion-activated Akt kinase prevents apoptosis in transgenic mouse hearts overexpressing insulin-like growth factor-1.

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.

• Authors: K Yamashita, J Kajstura, D J Discher, B J Wasserlauf, N H Bishopric, P Anversa, K A Webster
• Journal: Circulation research (Circ Res) Vol. 88 Issue 6 Pg. 609-14 (Mar 30 2001) ISSN: 1524-4571 [Electronic] United States
• PMID: 11282895 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Androstadienes
• Enzyme Inhibitors
• Imidazoles
• Proto-Oncogene Proteins
• Pyridines
• Insulin-Like Growth Factor I
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt
• Mitogen-Activated Protein Kinases
• p38 Mitogen-Activated Protein Kinases
• SB 203580
• Wortmannin

Topics

• 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, metabolism)
• Male
• Mice
• Mice, Transgenic
• Mitogen-Activated Protein Kinases (metabolism)
• Myocardial Ischemia (physiopathology)
• Myocardial Reperfusion
• Myocardium (metabolism, pathology)
• Perfusion
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins (metabolism)
• Proto-Oncogene Proteins c-akt
• Pyridines (pharmacology)
• Wortmannin
• p38 Mitogen-Activated Protein Kinases