Histone deacetylase inhibitors (HDACi) increase expression of KCa2.3 (SK3) in primary microvascular endothelial cells
Year: 2022
Type: article
Abstract: The small conductance calcium-activated potassium channel (KCa2.3) has long been recognized for its role in mediating vasorelaxation through the endothelium-derived hyperpolarization (EDH) response. Histone deacetylases (HDACs) have been implicated as potential modulators of blood pressure and histone deacetylase inhibitors (HDACi) are being explored as therapeutics for hypertension. Herein, we show that HDACi increase KCa2.3 expression when heterologously expressed in HEK cells and endogenously expressed in primary cultures of human umbilical vein endothelial cells (HUVECs) and human intestinal microvascular endothelial cells (HIMECs). When primary endothelial cells were exposed to HDACi, KCa2.3 transcripts, subunits, and functional current are increased. Quantitative RT-PCR (qPCR) demonstrated increased KCa2.3 mRNA following HDACi, confirming transcriptional regulation of KCa2.3 by HDACs. By using pharmacological agents selective for different classes of HDACs, we discriminated between cytoplasmic and epigenetic modulation of KCa2.3. Biochemical analysis revealed an association between the cytoplasmic HDAC6 and KCa2.3 in immunoprecipitation studies. Specifically inhibiting HDAC6 increases expression of KCa2.3. In addition to increasing the expression of KCa2.3, we show that nonspecific inhibition of HDACs causes an increase in the expression of the molecular chaperone Hsp70 in endothelial cells. When Hsp70 is inhibited in the presence of HDACi, the magnitude of the increase in KCa2.3 expression is diminished. Finally, we show a slower rate of endocytosis of KCa2.3 as a result of exposure of primary endothelial cells to HDACi. These data provide the first demonstrated approach to increase KCa2.3 channel number in endothelial cells and may partially account for the mechanism by which HDACi induce vasorelaxation.
Institutions: University of Pittsburgh, Magee-Womens Research Institute
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: U.S. Department of Defense, Cystic Fibrosis Foundation, American Heart Association, National Institutes of Health, National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: G1055318921, Role of MicroRNAs in Kidney Sodium Regulation, Iron Redox Regulation: Basic Mechanisms, Translational Implications and Strategies to Treat Cardiovascular Disease, G2520708964, Role of Xanthine Oxidase in Heme-induced Vascular Dysfunction, MECHANISM OF SYSTEMIC INFLAMMATION-ASSOCIATED ENDOTHELIAL AND EPITHELIAL CELL DYSFUNCTION FOLLOWING ACUTE PANCREATITIS, TRAUMA, AND BURNS, ACUTE PANCREATITIS AS A MODEL TO PREDICT TRANSITION OF SYSTEMIC INFLAMMATION TO ORGAN FAILURE IN TRAUMA AND CRITICAL ILLNESS, Women's Cardiovascular Health and Microvascular Mechanisms: Novel Insights from Pregnancy, Vascular Smooth Muscle and Blood Pressure Regulation By Cyb5R3², Glycocalyx in Pregnancy and the Preeclampsia Syndrome, G7861848135, G8383620969
OpenAlex ID: W4205787660