Role of protein phosphatases in hypoxic preconditioning.
To find a protein kinase C (PKC)-independent preconditioning mechanism, hypoxic preconditioning (HP; i.e., 10-min anoxia and 10-min reoxygenation) was applied to isolated rat hearts before 60-min global ischemia. HP led to improved recovery of developed pressure and reduced end-diastolic pressure in the left ventricle during reperfusion. Protection was unaffected by the PKC inhibitor bisindolylmaleimide (BIM; 1 micromol/l). It was abolished by the inhibitor of protein phosphatases 1 and 2A cantharidin (20 or 5 micromol/l) and partially enhanced by the inhibitor of protein phosphatase 2A okadaic acid (5 nmol/l). In adult rat cardiomyocytes treated with BIM and exposed to 60-min simulated ischemia (anoxia, extracellular pH 6.4), HP led to attenuation of anoxic Na(+)/Ca(2+) overload and of hypercontracture, which developed on reoxygenation. This protection was prevented by treatment with cantharidin but not with okadaic acid. In conclusion, HP exerts PKC-independent protection on ischemic-reperfused rat hearts and cardiomyocytes. Protein phosphatase 1 seems a mediator of this protective mechanism.
Ladilov
Yury
Y
Physiologisches Institut, Justus-Liebig-Universität, D-35392 Giessen, Germany.
Maxeiner
Hagen
H
Wolf
Christopher
C
Schäfer
Claudia
C
Meuter
Karsten
K
Piper
H Michael
HM
D000818:Animals; D002193:Cantharidin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000860:Hypoxia / Q000378:metabolism*; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D019194:Ischemic Preconditioning; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D018485:Muscle Fibers, Skeletal / Q000201:enzymology; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology / Q000201:enzymology*; D019319:Okadaic Acid / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2; D051381:Rats; D017208:Rats, Wistar; D017725:Ventricular Pressure
D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D019319:Okadaic Acid; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2; D002193:Cantharidin; C088060:bisindolylmaleimide