title: KCa 3.1 upregulation preserves endothelium-dependent vasorelaxation during aging and oxidative stress.
abstract: Endothelial oxidative stress develops with aging and reactive oxygen species impair endothelium-dependent relaxation (EDR) by decreasing nitric oxide (NO) availability. Endothelial KCa 3.1, which contributes to EDR, is upregulated by H2 O2 . We investigated whether KCa 3.1 upregulation compensates for diminished EDR to NO during aging-related oxidative stress. Previous studies identified that the levels of ceramide synthase 5 (CerS5), sphingosine, and sphingosine 1-phosphate were increased in aged wild-type and CerS2 mice. In primary mouse aortic endothelial cells (MAECs) from aged wild-type and CerS2 null mice, superoxide dismutase (SOD) was upregulated, and catalase and glutathione peroxidase 1 (GPX1) were downregulated, when compared to MAECs from young and age-matched wild-type mice. Increased H2 O2 levels induced Fyn and extracellular signal-regulated kinases (ERKs) phosphorylation and KCa 3.1 upregulation. Catalase/GPX1 double knockout (catalase(-/-) /GPX1(-/-) ) upregulated KCa 3.1 in MAECs. NO production was decreased in aged wild-type, CerS2 null, and catalase(-/-) /GPX1(-/-) MAECs. However, KCa 3.1 activation-induced, N(G) -nitro-l-arginine-, and indomethacin-resistant EDR was increased without a change in acetylcholine-induced EDR in aortic rings from aged wild-type, CerS2 null, and catalase(-/-) /GPX1(-/-) mice. CerS5 transfection or exogenous application of sphingosine or sphingosine 1-phosphate induced similar changes in levels of the antioxidant enzymes and upregulated KCa 3.1. Our findings suggest that, during aging-related oxidative stress, SOD upregulation and downregulation of catalase and GPX1, which occur upon altering the sphingolipid composition or acyl chain length, generate H2 O2 and thereby upregulate KCa 3.1 expression and function via a H2 O2 /Fyn-mediated pathway. Altogether, enhanced KCa 3.1 activity may compensate for decreased NO signaling during vascular aging.
authors.affiliation: Department of Physiology, Medical School, Ewha Womans University, Seoul, South Korea.
authors.forename: Shinkyu
authors.initials: S
authors.lastname: Choi
authors.affiliation: Department of Physiology, Medical School, Ewha Womans University, Seoul, South Korea.
authors.forename: Ji Aee
authors.initials: JA
authors.lastname: Kim
authors.affiliation: Department of Physiology, Medical School, Ewha Womans University, Seoul, South Korea.
authors.forename: Hai-Yan
authors.initials: HY
authors.lastname: Li
authors.affiliation: College of Pharmacy and MRC, Chungbuk National University, Chongju, South Korea.
authors.forename: Kyong-Oh
authors.initials: KO
authors.lastname: Shin
authors.affiliation: Department of Life Sciences, Ewha Womans University, Seoul, South Korea.
authors.forename: Goo Taeg
authors.initials: GT
authors.lastname: Oh
authors.affiliation: College of Pharmacy and MRC, Chungbuk National University, Chongju, South Korea.
authors.forename: Yong-Moon
authors.initials: YM
authors.lastname: Lee
authors.affiliation: Department of Molecular Medicine, Medical School, Ewha Womans University, Seoul, South Korea.
authors.forename: Seikwan
authors.initials: S
authors.lastname: Oh
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Yael
authors.initials: Y
authors.lastname: Pewzner-Jung
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Anthony H
authors.initials: AH
authors.lastname: Futerman
authors.affiliation: Department of Physiology, Medical School, Ewha Womans University, Seoul, South Korea.
authors.forename: Suk Hyo
authors.initials: SH
authors.lastname: Suh
mesh_terms: D000375:Aging / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001011:Aorta / Q000473:pathology; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D007213:Indomethacin / Q000494:pharmacology; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism*; D015640:Ion Channel Gating / Q000187:drug effects; D018345:Mice, Knockout; D008954:Models, Biological; D019335:Nitroarginine / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D010088:Oxidoreductases / Q000172:deficiency / Q000378:metabolism; D051076:Proto-Oncogene Proteins c-fyn / Q000378:metabolism; D013107:Sphingolipids / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
chemical_list: D000975:Antioxidants; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496925:Kcnn4 protein, mouse; D013107:Sphingolipids; D019335:Nitroarginine; D006861:Hydrogen Peroxide; D010088:Oxidoreductases; C108138:dihydroceramide desaturase; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn; D048049:Extracellular Signal-Regulated MAP Kinases; D007213:Indomethacin
keywords: Ca2+-activated K+ channel; aging; ceramide synthase 2 ablation; endothelial cells; oxidative stress; redox enzymes