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Novel cholesterol‐dependent regulation of cardioprotective K ATP subunit expression in HL‐1 cardiomyocytes
Author(s) -
Geiger Robert,
Fatima Naheed,
Flagg Thomas
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.750.24
Subject(s) - sterol regulatory element binding protein , transcription factor , trichostatin a , biology , cholesterol , gene expression , promoter , transactivation , microbiology and biotechnology , histone deacetylase , gene , chemistry , biochemistry , histone
Hypercholesterolemia is associated with poor cardiovascular health. In a recent study, we discovered that histone deacetylase inhibitors (HDIs) cause a significant depletion of cholesterol in HL‐1 cardiomyocytes that is associated with increased expression of the sulfonylurea receptor subunit (SUR2/ ABCC9 ) of the ATP‐sensitive potassium (K ATP ) channel. This implies that cellular cholesterol levels modulate the number of K ATP , which play a key role in protecting the heart from damage during stress. The mechanism by which cholesterol modulates SUR2 expression is unknown. Analysis of the sequence upstream of the SUR2 gene revealed binding sites for the cholesterol‐sensitive transcription factor, SREBP (Sterol Response Element Binding Protein), in the SUR2 promoter. Therefore, we tested the hypothesis that HDI‐dependent cholesterol depletion increases SUR2 by activating SREBP. As expected, treatment of HL‐1 cardiomyocytes with canonical HDI, trichostatin A (TSA; 30 ng/mL) for 72 hours caused a marked increase (20‐fold) of SUR2 mRNA expression compared to control. In addition, we observe increased activation of SREBP and marked increases in expression of selected SREBP‐target genes, including SCAP, IDOL, and PCSK9. Finally, in luciferase promoter assays, SREBP markedly increases reporter gene expression driven by the upstream SUR2 promoter (−510/−40) sequence, which contains a putative SREBP binding site. Taken together, our findings demonstrate a cholesterol‐dependent mechanism regulating expression of the cardioprotective K ATP channel and suggest a novel mechanism by which hypercholesterolemia may promote poor cardiovascular health. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .