Calcium/calmodulin-dependent protein kinase II mediates cardioprotection of intermittent hypoxia against ischemic-reperfusion-induced cardiac dysfunction.
Intermittent high-altitude (IHA) hypoxia-induced cardioprotection against ischemia-reperfusion (I/R) injury is associated with the preservation of sarcoplasmic reticulum (SR) function. Although Ca(2+)/calmodulin (CaM)-dependent protein kinase II (CaMKII) and phosphatase are known to modulate the function of cardiac SR under physiological conditions, the status of SR CaMKII and phosphatase during I/R in the hearts from IHA hypoxic rats is unknown. In the present study, we determined SR and cytosolic CaMKII activity during preischemia and I/R (30 min/30 min) in perfused hearts from normoxic and IHA hypoxic rats. The left ventricular contractile recovery, SR CaMKII activity as well as phosphorylation of phospholamban at Thr(17), and Ca(2+)/CaM-dependent SR Ca(2+)-uptake activity were depressed in the I/R hearts from normoxic rats, whereas these changes were prevented in the hearts from IHA hypoxic rats. Such beneficial effects of IHA hypoxia were lost by treating the hearts with a specific CaMKII inhibitor, KN-93. I/R also depressed cytosolic CaMKII and SR phosphatase activity, but these alterations remained unchanged in IHA hypoxic group. Furthermore, we found that the autophosphorylation at Thr(287), which confers Ca(2+)/CaM-independent activity, was not altered by I/R in both groups. These findings indicate that preservation of SR CaMKII activity plays an important role in the IHA hypoxia-induced cardioprotection against I/R injury via maintaining SR Ca(2+)-uptake activity.
Yu
Zhuo
Z
Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine and Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Ruijin Hospital, Shanghai, China.
Wang
Zhi-Hua
ZH
Yang
Huang-Tian
HT
D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D022162:Cytoplasmic Vesicles / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D000860:Hypoxia / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D009200:Myocardial Contraction / Q000502:physiology*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000503:physiopathology; D009206:Myocardium / Q000201:enzymology; D010766:Phosphorylation / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D013912:Threonine / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000378:metabolism* / Q000503:physiopathology; D016277:Ventricular Function, Left / Q000502:physiology; D000099211:Phospholamban; D000096926:Benzenesulfonamides
D001596:Benzylamines; D002118:Calcium; D002135:Calcium-Binding Proteins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D013912:Threonine; D000099211:Phospholamban; C072105:KN 93; D000096926:Benzenesulfonamides