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Targeted deletion of NF-[kappa]B p50 diminishes the cardioprotection of histone deacetylase inhibition
We have recently demonstrated that the inhibition of histone deacetylases (HDAC) protects the heart against ischemia-reperfusion (I/R) injury. The mechanism by which HDAC inhibition confers myocardial protection remains unknown. The purpose of this study is to investigate whether the disruption of N...
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Published in: | American journal of physiology. Heart and circulatory physiology 2010-06, Vol.298 (6), p.H2154 |
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Main Authors: | , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Online Access: | Get full text |
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Summary: | We have recently demonstrated that the inhibition of histone deacetylases (HDAC) protects the heart against ischemia-reperfusion (I/R) injury. The mechanism by which HDAC inhibition confers myocardial protection remains unknown. The purpose of this study is to investigate whether the disruption of NF-...B p50 would eliminate the protective effects of HDAC inhibition. Wild-type and NF-...B p50-deficient mice were treated with trichostatin A (TSA; 0.1 mg/kg ip), a potent inhibitor of HDACs. Twenty-four hours later, the hearts were perfused in Langendorff model and subjected to 30 min of ischemia and 30 min of reperfusion. Inhibition of HDACs by TSA in wild-type mice produced marked improvements in left ventricular end-diastolic pressure, left ventricular rate pressure product, and the reduction of infarct size compared with non-TSA-treated group. TSA-induced cardioprotection in wild-type animals was absent with genetic deletion of NF-...B p50 subunit. Notably, Western blot displayed a significant increase in nuclear NF-...B p50 and the immunoprecipitation demonstrated a remarkable acetylation of NF-...B p50 at lysine residues following HDAC inhibition. EMSA exhibited a subsequent increase in NF-...B DNA binding activity. Luciferase assay demonstrated an activation of NF-...B by HDAC inhibition. The pretreatment of H9c2 cardiomyoblasts with TSA (50 nmol/l) decreased cell necrosis and increased in cell viability in simulated ischemia. The resistance of H9c2 cardiomyoblasts to simulated ischemia by HDAC inhibition was eliminated by genetic knockdown of NF-...B p50 with transfection of NF- B p50 short interfering RNA but not scrambled short interfering RNA. These results suggest that NF-...B p50 acetylation and activation play a pivotal role in HDAC inhibition-induced cardioprotection. (ProQuest: ... denotes formulae/symbols omitted.) |
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ISSN: | 0363-6135 1522-1539 |