Inhibiting p90 Ribosomal S6 Kinase Prevents Na + -H + Exchanger–Mediated Cardiac Ischemia-Reperfusion Injury

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Abstract
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 P 2 O 2 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.

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