Back to Search
Start Over
The RSK Inhibitor BIX02565 Limits Cardiac Ischemia/Reperfusion Injury.
- Source :
- Journal of Cardiovascular Pharmacology & Therapeutics; Mar2016, Vol. 21 Issue 2, p177-186, 10p
- Publication Year :
- 2016
-
Abstract
- <bold>Aims: </bold>During ischemia/reperfusion (I/R), ribosomal S6 kinase (RSK) activates Na(+)/H(+) exchanger 1 (NHE1) by phosphorylating NHE1 at serine 703 (pS703-NHE1), which promotes cardiomyocyte death and injury. Pharmacologic inhibition of NHE1 effectively protects animal hearts from I/R. However, clinical trials using NHE1 inhibitors failed to show benefit in patients with acute myocardial infarction (MI). One possible explanation is those inhibitors block both agonist-stimulated activity (increasing I/R injury) and basal NHE1 activity (necessary for cell survival). We previously showed that dominant-negative RSK (DN-RSK) selectively blocked agonist-stimulated NHE1 activity. Therefore, we hypothesized that a novel RSK inhibitor (BIX02565) would blunt agonist-stimulated NHE1 and protect hearts from I/R.<bold>Methods and Results: </bold>Serum/angiotensin II-stimulated pS703-NHE1 was significantly decreased by BIX02565 in cultured cells. Intracellular pH recovery assay showed that BIX02565 selectively inhibited serum-stimulated NHE1 activity. Ischemia/reperfusion decreased left ventricular-developed pressure (LVDP; inhibited) to 8.7% of the basal level in non-transgenic littermate control (NLC) mouse hearts, which was significantly improved (44.6%) by BIX02565. Similar protection was observed in vehicle-treated, cardiac-specific DN-RSK-Tg mice (43%). No additional protective effect was seen in BIX02565-treated DN-RSK-Tg hearts. BIX02565 also improved LVDP in cardiac-specific wild-type (WT)-RSK-Tg mouse hearts (7.4%-40.9%, P < .01). Finally, Western Blotting results confirmed DN-RSK and BIX02565 significantly decreased I/R-induced pS703-NHE1.<bold>Conclusion: </bold>The RSK plays a crucial role in I/R-induced activation of NHE1 and cardiac injury. The RSK inhibition may provide an alternative target for patients with MI. [ABSTRACT FROM AUTHOR]
- Subjects :
- MYOCARDIAL infarction
REPERFUSION injury
ISCHEMIA
HEART cells
ANGIOTENSIN II
PATIENTS
AMINO acids
ANIMAL experimentation
AZEPINES
CELL culture
COMPARATIVE studies
DOSE-effect relationship in pharmacology
EPITHELIAL cells
HAMSTERS
HETEROCYCLIC compounds
RESEARCH methodology
MEDICAL cooperation
MICE
MYOCARDIAL reperfusion complications
RATS
RESEARCH
RESEARCH funding
RODENTS
TRANSFERASES
EVALUATION research
THERAPEUTICS
Subjects
Details
- Language :
- English
- ISSN :
- 10742484
- Volume :
- 21
- Issue :
- 2
- Database :
- Complementary Index
- Journal :
- Journal of Cardiovascular Pharmacology & Therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 113248973
- Full Text :
- https://doi.org/10.1177/1074248415591700