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Calcium/calmodulin-dependent protein kinase II mediates cardioprotection of intermittent hypoxia against ischemic-reperfusion-induced cardiac dysfunction.

Abstract
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.
AuthorsZhuo Yu, Zhi-Hua Wang, Huang-Tian Yang
JournalAmerican journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 297 Issue 2 Pg. H735-42 (Aug 2009) ISSN: 1522-1539 [Electronic] United States
PMID19525372 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Benzylamines
  • Calcium-Binding Proteins
  • Protein Kinase Inhibitors
  • Sulfonamides
  • phospholamban
  • KN 93
  • Threonine
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Calcium
Topics
  • Animals
  • Benzylamines (pharmacology)
  • Calcium (metabolism)
  • Calcium-Binding Proteins (metabolism)
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 (antagonists & inhibitors, metabolism)
  • Cytoplasmic Vesicles (metabolism)
  • Cytosol (metabolism)
  • Hypoxia (metabolism, physiopathology)
  • Male
  • Myocardial Contraction (physiology)
  • Myocardial Reperfusion Injury (metabolism, physiopathology)
  • Myocardium (enzymology)
  • Phosphorylation (physiology)
  • Protein Kinase Inhibitors (pharmacology)
  • Rats
  • Rats, Sprague-Dawley
  • Sarcoplasmic Reticulum (metabolism)
  • Sulfonamides (pharmacology)
  • Threonine (metabolism)
  • Ventricular Dysfunction, Left (metabolism, physiopathology)
  • Ventricular Function, Left (physiology)

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