© 2001 American Heart Association, Inc.
Cellular Biology |
Reperfusion-Activated Akt Kinase Prevents Apoptosis in Transgenic Mouse Hearts Overexpressing Insulin-Like Growth Factor-1
Presented in part at the 73rd Scientific Sessions of the American Heart Association, New Orleans, La, November 12–15, 2000, and published in abstract form (Circulation. 2000;102[suppl II]:II-214).
From the Department of Molecular and Cellular Pharmacology (K.Y., D.J.D., B.J.W., N.H.B., K.A.W.), University of Miami Medical Center, Miami, Fla, and the Department of Medicine (J.K., P.A.), New York Medical College, Valhalla, NY.
Correspondence to K.A. Webster, Department of Molecular and Cellular Pharmacology, University of Miami Medical Center, RMSB 6038, Miami, FL 33136. E-mail Kwebster{at}chroma.med.miami.edu
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 µmol/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.
Key Words: ischemia • hypoxia • phosphoinositol-3'-kinase • p38 mitogen-activated protein kinase • SB203580
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