Open AccessNovel cholesterol‐dependent regulation of cardiac K ATP subunit expression revealed using histone deacetylase inhibitors
Author(s) -
Geiger Robert,
Fatima Naheed,
Schooley James F.,
Smyth Jeremy T.,
Haigney Mark C.,
Flagg Thomas P.
Publication year - 2021
Publication title -
physiological reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.918
H-Index - 39
ISSN - 2051-817X
DOI - 10.14814/phy2.14675
Subject(s) - trichostatin a , sterol regulatory element binding protein , histone deacetylase , transcription factor , cholesterol , gene expression , chemistry , regulation of gene expression , histone deacetylase inhibitor , biology , microbiology and biotechnology , endocrinology , medicine , histone , sterol , biochemistry , gene
We recently discovered that the histone deacetylase inhibitor, trichostatin A (TSA), increases expression of the sulfonylurea receptor 2 (SUR2; Abcc9 ) subunit of the ATP‐sensitive K + (K ATP ) channel in HL‐1 cardiomyocytes. Interestingly, the increase in SUR2 was abolished with exogenous cholesterol, suggesting that cholesterol may regulate channel expression. In the present study, we tested the hypothesis that TSA increases SUR2 by depleting cholesterol and activating the sterol response element binding protein (SREBP) family of transcription factors. Treatment of HL‐1 cardiomyocytes with TSA (30 ng/ml) caused a time‐dependent increase in SUR2 mRNA expression that correlates with the time course of cholesterol depletion assessed by filipin staining. Consistent with the cholesterol‐dependent regulation of SREBP increasing SUR2 mRNA expression, we observe a significant increase in SREBP cleavage and translocation to the nucleus following TSA treatment that is inhibited by exogenous cholesterol. Further supporting the role of SREBP in mediating the effect of TSA on K ATP subunit expression, SREBP1 significantly increased luciferase reporter gene expression driven by the upstream SUR2 promoter. Lastly, HL‐1 cardiomyocytes treated with the SREBP inhibitor PF429242 significantly suppresses the effect of TSA on SUR2 gene expression. These results demonstrate that SREBP is an important regulator of K ATP channel expression and suggest a novel method by which hypercholesterolemia may exert negative effects on the cardiovascular system, namely, by suppressing expression of the K ATP channel.