Inhibition of apoptotic protein p53 lowers the threshold of isoflurane-induced cardioprotection during early reperfusion in rabbits.
BACKGROUND
Exposure to isoflurane before and during early reperfusion protects against myocardial infarction by activating phosphatidylinositol-3-kinase (PI3K)-mediated signaling. The apoptotic protein, p53, is regulated by PI3K, and inhibition of p53 protects against ischemic injury. We tested the hypothesis that p53 inhibition lowers the threshold of isoflurane-induced postconditioning in vivo.


METHODS
Rabbits (n = 73) instrumented for hemodynamic measurement and subjected to a 30-min left anterior descending coronary artery occlusion and 3-h reperfusion received 0.9% saline (control), isoflurane (0.5 or 1.0 minimum alveolar concentration [MAC]) administered for 3 min before and 2 min after reperfusion, the p53 inhibitor pifithrin-alpha (1.5 or 3.0 mg/kg), or 0.5 MAC isoflurane plus 1.5 mg/kg pifithrin-alpha. Other rabbits received 3.0 mg/kg pifithrin-alpha or 0.5 MAC isoflurane plus 1.5 mg/kg pifithrin-alpha after pretreatment with the selective PI3K inhibitor wortmannin (0.6 mg/kg) or the mitochondrial permeability transition pore opener atractyloside (5 mg/kg).


RESULTS
Isoflurane (1.0 but not 0.5 MAC), pifithrin-alpha (3.0 but not 1.5 mg/kg), and the combination of 0.5 MAC isoflurane plus 1.5 mg/kg pifithrin-alpha significantly (P < 0.05) reduced infarct size (21% +/- 4%, 43% +/- 7%, 22% +/- 4%, 45% +/- 4%, and 28% +/- 3% [mean +/- sd], respectively, of left ventricular area at risk; triphenyltetrazolium chloride staining) when compared with control (45% +/- 2%). Atractyloside, but not wortmannin, abolished 3.0 mg/kg pifithrin-alpha-induced cardioprotection, whereas atractyloside and wortmannin blocked reductions in infarct size produced by 0.5 MAC isoflurane plus 1.5 mg/kg pifithrin-alpha.


CONCLUSIONS
The results indicate that inhibition of the apoptotic protein p53 lowers the threshold of isoflurane-induced cardioprotection during early reperfusion in vivo.
Venkatapuram
Suneetha
S
Wang
Chen
C
Krolikowski
John G
JG
Weihrauch
Dorothee
D
Kersten
Judy R
JR
Warltier
David C
DC
Pratt
Phillip F
PF
Pagel
Paul S
PS
D000818:Animals; D052160:Benzothiazoles / Q000494:pharmacology; D038341:Glycogen Synthase Kinases / Q000502:physiology; D019157:Ischemic Preconditioning, Myocardial; D007530:Isoflurane / Q000494:pharmacology*; D008297:Male; D033681:Mitochondrial Membrane Transport Proteins / Q000502:physiology*; D000083162:Mitochondrial Permeability Transition Pore; D009203:Myocardial Infarction / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010766:Phosphorylation; D011817:Rabbits; D014050:Toluene / Q000031:analogs & derivatives / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors*
D052160:Benzothiazoles; D038341:Glycogen Synthase Kinases; D007530:Isoflurane; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D019869:Phosphatidylinositol 3-Kinases; D014050:Toluene; D016159:Tumor Suppressor Protein p53; C121565:pifithrin