PI 3-kinase regulates the mitochondrial transition pore in controlled reperfusion and postconditioning

Jean Chrisostome Bopassa, René Ferrera, Odile Gateau-Roesch, Elisabeth Couture-Lepetit, Michel Ovize

Research output: Contribution to journalArticlepeer-review

183 Scopus citations

Abstract

Objective: We investigated whether phosphatidylinositol 3-kinase (PI3K) might regulate mitochondrial permeability transition pore (mPTP) opening in hearts reperfused with either low pressure or postconditioning. Methods: Male Wistar rat hearts (n = 72) were perfused according to the Langendorff technique, exposed to 30 min of ischemia, and assigned to one of the following groups: (1) reperfusion with normal pressure (NP; 100 cm H2O), (2) reperfusion with low pressure (LP; 70 cm H2O), or reperfusion with postconditioning, i.e. 3 episodes of 30 s reperfusion followed by 30 s of ischemia (PostC). Hearts received either the PI3K inhibitors wortmannin or LY294002, or vehicle at the onset of the 60 min reperfusion. Postischemic functional recovery was assessed by rate-pressure product (RPP), and irreversible injury by lactate dehydrogenase (LDH), creatine kinase (CK) and troponin I (TnI) release. Mitochondria were isolated from the reperfused myocardium, and Ca2+-induced mPTP opening was measured using a potentiometric method. Results: Functional recovery was significantly improved in LP and PostC hearts with RPP averaging 13,880 ± 810 (LP) and 17,130 ± 900 mm Hg × beats/min (PostC) versus 6450 ± 500 mm Hg × beats/min in NP hearts (p < 0.01). LDH release averaged 230 ± 30 and 145 ± 15 IU/h/g of myocardial tissue in LP and PostC versus 340 ± 10 IU/h/g in NP (p < 0.05). Wortmannin and LY294002 prevented both RPP improvement and decrease in LDH, CK, and TnI release in LP and PostC groups. The Ca2+ load required to induce mPTP opening averaged 58 ± 3 and 52 ± 1 nmol/mg mitochondrial proteins in LP and PostC groups, respectively, versus 35 ± 4 nmol/mg in the NP group (p < 0.01). Wortmannin and LY294002 prevented the beneficial effect in both the LP and PostC groups. Conclusion: These results suggest that PI3K regulates the opening of the mitochondrial permeability transition pore in rat hearts reperfused with low pressure or postconditioning.

Original languageEnglish (US)
Pages (from-to)178-185
Number of pages8
JournalCardiovascular Research
Volume69
Issue number1
DOIs
StatePublished - Jan 2006
Externally publishedYes

Keywords

  • Ischemia
  • Postconditioning
  • Reperfusion

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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