ArticleJournal of cardiovascular pharmacology and therapeutics2016
The RSK Inhibitor BIX02565 Limits Cardiac Ischemia/Reperfusion Injury.
Article in Journal of cardiovascular pharmacology and therapeutics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 14 citations in OpenAlex.
- Discovery of sulfonyl benzoic acid derivatives with joint TGR5-agonist and FXR-antagonist activity for myocardial ischemia/reperfusion injury protection.Acta pharmaceutica Sinica. B · 2026Article
- Phosphorylation of UDP-glucose dehydrogenase increases glycosaminoglycan biosynthesis and promotes tumor cell motility, spheroid growth, and therapeutic resistance.Matrix biology : journal of the International Society for Matrix Biology · 2025Article
- RSK1 and RSK2 as therapeutic targets: an up-to-date snapshot of emerging data.Expert opinion on therapeutic targets · 2024Review
- Therapeutic targeting of p90 ribosomal S6 kinase.Frontiers in cell and developmental biology · 2023Review
- The Remaining Conundrum of the Role of the NaReviews in cardiovascular medicine · 2022Review
- Activation of RSK2 upregulates SOX8 to promote methotrexate resistance in gestational trophoblastic neoplasia.Laboratory investigation; a journal of technical methods and pathology · 2021Article
- Structural and Functional Changes in the NaInternational journal of molecular sciences · 2019Review
- Role of p90RSK in Kidney and Other Diseases.International journal of molecular sciences · 2019Review
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
Abstract
aimsDuring 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. METHODS AND
resultsSerum/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.
conclusionThe 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.
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