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

Kazuhito Yamashita, Jan Kajstura, Daryl J. Discher, Bernard J. Wasserlauf, Nanette H. Bishopric, Piero Anversa, Keith A. Webster

Research output: Contribution to journalArticlepeer-review

124 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)609-614
Number of pages6
JournalCirculation research
Volume88
Issue number6
DOIs
StatePublished - Mar 30 2001

Keywords

  • Hypoxia
  • Ischemia
  • p38 mitogen-activated protein kinase
  • Phosphoinositol-3′-kinase
  • SB203580

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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