TY - JOUR
T1 - P90 ribosomal S6 kinase regulates activity of the renin-angiotensin system
T2 - A pathogenic mechanism for ischemia-reperfusion injury
AU - Shi, Xi
AU - Yan, Chen
AU - Nadtochiy, Sergiy M.
AU - Abe, Jun Ichi
AU - Brookes, Paul S.
AU - Berk, Bradford C.
N1 - Funding Information:
We thank Novartis for providing aliskiren (Tekturna, Novartis Pharmaceuticals Corporation, East Hanover, NJ) for this study. This work was also supported by NIH grant HL63462 (to B.C.B), HL088400 (to C.Y.) and HL-07115 (to P.S.B.).
Funding Information:
This work was done with the support from Novartis.
PY - 2011/8
Y1 - 2011/8
N2 - 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.
AB - 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.
KW - Aliskiren
KW - Ischemia-reperfusion
KW - RSK
KW - Renin
KW - Renin-angiotensin system
UR - http://www.scopus.com/inward/record.url?scp=79959492923&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79959492923&partnerID=8YFLogxK
U2 - 10.1016/j.yjmcc.2011.05.005
DO - 10.1016/j.yjmcc.2011.05.005
M3 - Article
C2 - 21609719
AN - SCOPUS:79959492923
SN - 0022-2828
VL - 51
SP - 272
EP - 275
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
IS - 2
ER -