Novel cholesterol‐dependent regulation of cardiac KATP subunit expression revealed using histone deacetylase inhibitors

• Published in: Physiological reports 2021-01, Vol.8 (24), p.e14675-n/a
• Main Authors: Geiger, Robert, Fatima, Naheed, Schooley, James F., Smyth, Jeremy T., Haigney, Mark C., Flagg, Thomas P.
• Format: Article
• Language: English
• Subjects: Abcc9; Antibodies; Cardiomyocytes; Cardiovascular system; Cholesterol; Experiments; Gene expression; Heart; Histone deacetylase; Hypercholesterolemia; Hypotheses; Ischemia; Localization; Metabolism; Original Research; Physiology; Potassium; Proteins; Reporter gene; SREBP; Sterol regulatory element-binding protein; Sterols; Sulfonylurea; SUR2; Transcription factors; Trichostatin A
• ISSN: 2051-817X
• DOI: 10.14814/phy2.14675

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+ (KATP) 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 KATP 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 KATP channel expression and suggest a novel method by which hypercholesterolemia may exert negative effects on the cardiovascular system, namely, by suppressing expression of the KATP channel. The ATP‐sensitive potassium (KATP) channel can protect the heart during metabolic challenges. Our study shows that SREBP is a regulator of cardiac KATP channel expression and suggests a novel method by which hypercholesterolemia may exert negative effects on the cardiovascular system, namely, by suppressing expression of the KATP channel.