PMID- 16717153
OWN - NLM
STAT- MEDLINE
DCOM- 20060620
LR  - 20171116
IS  - 1524-4539 (Electronic)
IS  - 0009-7322 (Linking)
VI  - 113
IP  - 21
DP  - 2006 May 30
TI  - Inhibiting p90 ribosomal S6 kinase prevents (Na+)-H+ exchanger-mediated cardiac 
      ischemia-reperfusion injury.
PG  - 2516-23
AB  - 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 micromol/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.
FAU - Maekawa, Naoya
AU  - Maekawa N
AD  - Cardiovascular Research Institute, Department of Medicine, University of 
      Rochester, Rochester, NY, USA.
FAU - Abe, Jun-ichi
AU  - Abe J
FAU - Shishido, Tetsuro
AU  - Shishido T
FAU - Itoh, Seigo
AU  - Itoh S
FAU - Ding, Bo
AU  - Ding B
FAU - Sharma, Virendra K
AU  - Sharma VK
FAU - Sheu, Shey-Shing
AU  - Sheu SS
FAU - Blaxall, Burns C
AU  - Blaxall BC
FAU - Berk, Bradford C
AU  - Berk BC
LA  - eng
GR  - R01 HL033333/HL/NHLBI NIH HHS/United States
GR  - GM71985/GM/NIGMS NIH HHS/United States
GR  - HL44721/HL/NHLBI NIH HHS/United States
GR  - HL66919/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20060522
PL  - United States
TA  - Circulation
JT  - Circulation
JID - 0147763
RN  - 0 (Cation Transport Proteins)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Membrane Proteins)
RN  - 0 (Slc9a1 protein, mouse)
RN  - 0 (Sodium-Hydrogen Exchanger 1)
RN  - 0 (Sodium-Hydrogen Exchangers)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 90-kDa)
SB  - IM
CIN - Circulation. 2009 Oct 13;120(15):e137; author reply e138. PMID: 19822814
MH  - Animals
MH  - Apoptosis
MH  - Cation Transport Proteins/metabolism
MH  - Enzyme Inhibitors
MH  - Membrane Proteins/metabolism
MH  - Mice
MH  - Mice, Transgenic
MH  - Myocardial Reperfusion Injury/etiology/*prevention & control
MH  - Myocytes, Cardiac/pathology
MH  - Phosphorylation
MH  - Rats
MH  - Ribosomal Protein S6 Kinases, 90-kDa/*antagonists & inhibitors
MH  - Sodium-Hydrogen Exchanger 1
MH  - Sodium-Hydrogen Exchangers/metabolism/*physiology
MH  - Transduction, Genetic
EDAT- 2006/05/24 09:00
MHDA- 2006/06/21 09:00
CRDT- 2006/05/24 09:00
PHST- 2006/05/24 09:00 [pubmed]
PHST- 2006/06/21 09:00 [medline]
PHST- 2006/05/24 09:00 [entrez]
AID - CIRCULATIONAHA.105.563486 [pii]
AID - 10.1161/CIRCULATIONAHA.105.563486 [doi]
PST - ppublish
SO  - Circulation. 2006 May 30;113(21):2516-23. doi: 10.1161/CIRCULATIONAHA.105.563486. 
      Epub 2006 May 22.