{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T01:20:19Z","timestamp":1793064019720,"version":"4.5.0"},"reference-count":74,"publisher":"American Physiological Society","issue":"5","funder":[{"DOI":"10.13039\/100000050","name":"NHLBI","doi-asserted-by":"crossref","award":["HL042220"],"award-info":[{"award-number":["HL042220"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Joseph C Georg Fund"},{"name":"Health Science Center Foundation at Syracuse"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Heart and Circulatory Physiology"],"published-print":{"date-parts":[[2016,11,1]]},"abstract":"<jats:p> Histone deacetylase (HDAC) inhibitors are small molecule anticancer therapeutics that exhibit limiting cardiotoxicities including QT interval prolongation and life-threatening cardiac arrhythmias. Because the molecular mechanisms for HDAC inhibitor-induced cardiotoxicity are poorly understood, we performed whole cell patch voltage-clamp experiments to measure cardiac sodium currents ( I<jats:sub>Na<\/jats:sub>) from wild-type neonatal mouse ventricular or human-induced pluripotent stem cell-derived cardiomyocytes treated with trichostatin A (TSA), vorinostat (VOR), or romidepsin (FK228). All three pan-HDAC inhibitors dose dependently decreased peak I<jats:sub>Na<\/jats:sub> density and shifted the voltage activation curve 3- to 8-mV positive. Increases in late I<jats:sub>Na<\/jats:sub> were not observed despite a moderate slowing of the inactivation rate at low activating potentials (&lt;\u221240 mV). Scn5a mRNA levels were not significantly altered but Na<jats:sub>V<\/jats:sub>1.5 protein levels were significantly reduced. Immunoprecipitation with anti-Na<jats:sub>V<\/jats:sub>1.5 and Western blotting with anti-acetyl-lysine antibodies indicated that Na<jats:sub>V<\/jats:sub>1.5 acetylation is increased in vivo after HDAC inhibition. FK228 inhibited total cardiac HDAC activity with two apparent IC<jats:sub>50<\/jats:sub>s of 5 nM and 1.75 \u03bcM, consistent with previous findings with TSA and VOR. FK228 also decreased ventricular gap junction conductance ( g<jats:sub>j<\/jats:sub>), again consistent with previous findings. We conclude that pan-HDAC inhibition reduces cardiac I<jats:sub>Na<\/jats:sub> density and Na<jats:sub>V<\/jats:sub>1.5 protein levels without affecting late I<jats:sub>Na<\/jats:sub> amplitude and, thus, probably does not contribute to the reported QT interval prolongation and arrhythmias associated with pan-HDAC inhibitor therapies. Conversely, reductions in g<jats:sub>j<\/jats:sub> may enhance the occurrence of triggered activity by limiting electrotonic inhibition and, combined with reduced I<jats:sub>Na<\/jats:sub>, slow myocardial conduction and increase vulnerability to reentrant arrhythmias. <\/jats:p>","DOI":"10.1152\/ajpheart.00156.2016","type":"journal-article","created":{"date-parts":[[2016,9,16]],"date-time":"2016-09-16T22:49:33Z","timestamp":1474066173000},"page":"H1139-H1149","source":"Crossref","is-referenced-by-count":32,"title":["Changes in cardiac Na<sub>v<\/sub>1.5 expression, function, and acetylation by pan-histone deacetylase  inhibitors"],"prefix":"10.1152","volume":"311","author":[{"given":"Qin","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Pharmacology, State University of New York (SUNY) Upstate Medical University, Syracuse, New York; 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