on May 22, 2006
Published online before print May 22, 2006, doi: 10.1161/CIRCULATIONAHA.105.563486
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Submitted on December 22, 2004
From the Cardiovascular Research Institute and Departments of Medicine and Pharmacology/Physiology (V.K.S., S.-S.S.), University of Rochester, Rochester, NY. * To whom correspondence should be addressed. E-mail: Bradford_berk{at}urmc.rochester.edu.
Background--Pharmacological and genetic studies indicate that the Na+-H+ exchanger isoform 1 (NHE1) plays a critical role in myocardial ischemia and reperfusion (I/R) injury. We found that p90 ribosomal S6 kinase (RSK) phosphorylated serine 703 of NHE1, stimulating 14-3-3 binding and NHE1 activity. Therefore, we hypothesized that inhibiting RSK in cardiomyocytes would prevent NHE1 activation and decrease I/R-mediated injury. Methods and Results--To examine the role of RSK in vivo, we generated transgenic mice with cardiac-specific overexpression of dominant negative RSK (DN-RSK-TG). DN-RSK-TG hearts demonstrated normal basal cardiac function and morphology. However, myocardial infarction (left coronary artery occlusion for 45 minutes) in DN-RSK-TG hearts was significantly reduced at 24 hours of reperfusion from 46.9±5.6% area at risk in nontransgenic littermate controls to 26.0±4.2% in DN-RSK-TG (P<0.01). Cardiomyocyte apoptosis was significantly reduced after I/R in DN-RSK (0.9±0.2%) compared with nontransgenic littermate controls (6.2±2.6%). Importantly, activation of RSK and interaction of 14-3-3 with NHE1, necessary for agonist-stimulated NHE1 activity, were increased by I/R and inhibited by 70% in DN-RSK-TG (P<0.01). Next, we transduced rat neonatal cardiomyocytes with adenovirus-expressing DN-RSK (Ad.DN-RSK) and measured NHE1 activity. The baseline rate of pH recovery in acid-loaded cells was equal in cells expressing LacZ or DN-RSK. However, NHE1 activation by 100 µmol/L H2O2 was significantly inhibited in cells expressing DN-RSK (0.16±0.02 pH units/min) compared with Ad.LacZ (0.49±0.13 pH units/min). Apoptosis induced by 12 hours of anoxia followed by 24 hours’ reoxygenation was significantly reduced in cells expressing Ad.DN-RSK (18.6±2.0%) compared with Ad.LacZ (29.3±5.4%). Conclusions--In summary, RSK is a novel regulator of cardiac NHE1 activity by phosphorylating NHE1 serine 703 and a new pathological mediator of I/R injury in the heart.
Revised on March 16, 2006
Accepted on March 17, 2006
Inhibiting p90 Ribosomal S6 Kinase Prevents Na+-H+ Exchanger-Mediated Cardiac Ischemia-Reperfusion Injury
Naoya Maekawa PhD,
Key words: heart • ischemia • Na+-H+ exchanger • reperfusion • ribosomal S6 kinases
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