P90 ribosomal S6 kinase regulates activity of the renin-angiotensin system: A pathogenic mechanism for ischemia-reperfusion injury

Xi Shi, Chen Yan, Sergiy M. Nadtochiy, Jun Ichi Abe, Paul S. Brookes, Bradford C. Berk

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Increasing evidence suggests that local renin-angiotensin system (RAS) plays an important role in cardiac diseases. Elevated p90 ribosomal S6 kinase (RSK) activity has been observed in diabetic animal, as well as in human failing hearts. We hypothesize that RSK mediates cardiac dysfunction by up regulating local RAS signaling. In the present study, we show that the prorenin mRNA level was significantly increased (~. 5.6-fold) in transgenic mouse hearts with cardiac specific expression of RSK (RSK-Tg). The RSK-Tg mice were more vulnerable to ischemia/reperfusion (I/R) injury than non-transgenic littermate controls (NLC). To further understand the direct contribution of cardiac renin to I/R injury, we used a Langendorff system to evaluate the effect of renin inhibition by aliskiren in RSK-Tg mouse hearts. In the vehicle-perfused group, I/R significantly decreased left ventricular developed pressure (LVDP) in RSK-Tg hearts compared to NLC (7% versus 60% of the baseline). However, aliskiren perfusion significantly increased LVDP in RSK-Tg (7% to 61%, p< 0.01) but not in NLC hearts (60% to 62%, n.s.). The protective effect of aliskiren in RSK-Tg hearts was further demonstrated with positive (contraction) d. p/d. t (6.5% to 63%, p< 0.01) and rate pressure product (RPP) (5% to 51%, p< 0.01). Moreover, aliskiren significantly decreased I/R induced infarction in RSK-Tg (60% to 32%, p< 0.01), compared to NLC hearts (37% to 32%, n.s.). These results suggest that RSK plays a crucial role in regulating local cardiac renin, which contributes to I/R induced cardiac injury and dysfunction. Thus, renin inhibition may provide an alternative therapeutic strategy under conditions of increased RAS.

Original languageEnglish (US)
Pages (from-to)272-275
Number of pages4
JournalJournal of Molecular and Cellular Cardiology
Volume51
Issue number2
DOIs
StatePublished - Aug 2011
Externally publishedYes

Keywords

  • Aliskiren
  • Ischemia-reperfusion
  • RSK
  • Renin
  • Renin-angiotensin system

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Fingerprint

Dive into the research topics of 'P90 ribosomal S6 kinase regulates activity of the renin-angiotensin system: A pathogenic mechanism for ischemia-reperfusion injury'. Together they form a unique fingerprint.

Cite this