RSK: a Pathogenic Mediator and Potential Drug Target in Cardiac Ischemia/Reperfusion Injury

Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Pharmacology and Physiology, 2011.Cardiac remodeling including hypertrophy and apoptosis following myocardial infarction (MI) leads to congestive heart failure, which is a major cause of morbidity and mortality following MI. Many factors, for instance, reactive oxygen species (ROS), renin-angiotensin signaling (RAS) are reported as regulators in the cardiac remodeling process. Previous studies in our laboratory showed an elevated p90 ribosomal S6 Kinase (RSK) activity in animal and human failing hearts. However, the precise role of p90RSK has not been well studied yet. We proposed that RSK contributes to cardiac injury and pathological cardiac remodeling by regulating local RAS and Na+/H+ exchanger 1 (NHE1) activation. To study this, we used transgenic mice that over express p90RSK (WT-RSK-Tg) or dominant negative form of RSK (DN-RSK-Tg) specifically in cardiac myocytes. First, we demonstrated that RSK up-regulates prorenin and local RAS, which contributes to accelerate cardiac ischemia/reperfusion (I/R) injury. Renin inhibitor aliskiren significantly increases cardiac functional recovery in WT-RSK-Tg mice after I/R. Second, we found that up regulated angiotensin-converting enzyme (ACE) in WT-RSK-Tg hearts, as well as in normal mouse hearts with MI. In cultured cardiomyocyte, Angiotensin II (Ang II) stimulated ACE up regulation is enhanced by over expressing WT-RSK, and blunted by DN-RSK and RSK inhibitor. In addition, MI induced cardiac remodeling and dysfunction is significantly reduced in DN-RSK-Tg. Third, we proved that inhibiting RSK activity by DN-RSK-Tg or RSK inhibitor provides similar cardiac protection in mice with I/R. This is possibly mediated by inhibiting I/R induced NHE1 activation. In conclusion, we found that RSK plays a crucial role in both acute and chronic MI, which may provide new therapeutic approaches for treating cardiac diseases