Role of Protein Kinase C in Metabolic Regulation of Coronary Endothelial Small Conductance Calcium‐Activated Potassium Channels

作者：Hang Xing, Sharif A. Sabe, Guangbin Shi, Dwight D. Harris, Yuhong Liu, Frank W. Sellke, Jun Feng · 发表于：Journal of the American Heart Association · 年份：2024 · DOI：10.1161/jaha.123.031028 · 被引用次数：9 · 研究领域：Ion channel regulation and function、Nitric Oxide and Endothelin Effects、Calcium signaling and nucleotide metabolism

Background Small conductance calcium‐activated potassium (SK) channels are largely responsible for endothelium‐dependent coronary arteriolar relaxation. Endothelial SK channels are downregulated by the reduced form of nicotinamide adenine dinucleotide (NADH), which is increased in the setting of diabetes, yet the mechanisms of these changes are unclear. PKC (protein kinase C) is an important mediator of diabetes‐induced coronary endothelial dysfunction. Thus, we aimed to determine whether NADH signaling downregulates endothelial SK channel function via PKC. Methods and Results SK channel currents of human coronary artery endothelial cells were measured by whole cell patch clamp method in the presence/absence of NADH, PKC activator phorbol 12‐myristate 13‐acetate, PKC inhibitors, or endothelial PKC α /PKC β knockdown by using small interfering RNA. Human coronary arteriolar reactivity in response to the selective SK activator NS309 was measured by vessel myography in the presence of NADH and PKC β inhibitor LY333531. NADH (30–300 μmol/L) or PKC activator phorbol 12‐myristate 13‐acetate (30–300 nmol/L) reduced endothelial SK current density, whereas the selective PKC ᵦ inhibitor LY333531 significantly reversed the NADH‐induced SK channel inhibition. PKC β small interfering RNA, but not PKC α small interfering RNA, significantly prevented the NADH‐ and phorbol 12‐myristate 13‐acetate–induced SK inhibition. Incubation of human coronary artery endothelial cells with NADH significa...