Cholesterol regulates cardiac KATP subunit expression through an SREBP‐dependent mechanism

Abstract

We recently discovered that the histone deacetylase inhibitor, trichostatin A (TSA), increases the expression of the sulfonylurea receptor 2 (SUR2; Abcc9) subunit of the ATP‐sensitive K+ (KATP) channel in HL‐1 cardiomyocytes. Importantly, the effects of TSA were abolished if cells were treated with exogenous cholesterol, suggesting that cholesterol may suppress 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. As expected, 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. This is specific for SUR2 and we observe little or no change in expression of the SUR1 subunit. Consistent with a central role for cholesterol‐dependent activation of SREBP in driving the increase in SUR2 mRNA expression, we observe a marked increase in the cleavage of SREBP1 following TSA, and this is inhibited by addition of cholesterol to the media. Further supporting the role of SREBP following TSA treatment, we observe increased expression of other SREBP‐dependent genes including PCSK9 and inducible degrader of LDLr (IDOL). Lastly, in luciferase promoter assays SREBP‐1a markedly increased reporter gene expression driven by the upstream SUR2, but not SUR1, promoter. Taken together, our data are consistent with the conclusion that cholesterol depletion by TSA leads to activation the SREBP signaling pathway that directly acts on the SUR2 promoter to increase gene expression. This finding suggests a novel means by which hypercholesterolemia may exert negative effects on the cardiovascular system by suppressing expression of the KATP channel.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.