Open AccessK Ca 3.1 upregulation preserves endothelium‐dependent vasorelaxation during aging and oxidative stress
Author(s) -
Choi Shinkyu,
Kim Ji Aee,
Li Haiyan,
Shin KyongOh,
Oh Goo Taeg,
Lee YongMoon,
Oh Seikwan,
PewznerJung Yael,
Futerman Anthony H.,
Suh Suk Hyo
Publication year - 2016
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.12502
Subject(s) - downregulation and upregulation , superoxide dismutase , oxidative stress , biology , sphingosine , gpx1 , sphingosine kinase 1 , catalase , reactive oxygen species , glutathione peroxidase , endocrinology , microbiology and biotechnology , biochemistry , sphingosine 1 phosphate , receptor , gene
Summary Endothelial oxidative stress develops with aging and reactive oxygen species impair endothelium‐dependent relaxation ( EDR ) by decreasing nitric oxide ( NO ) availability. Endothelial K Ca 3.1, which contributes to EDR , is upregulated by H 2 O 2 . We investigated whether K Ca 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 ( MAEC s) from aged wild‐type and CerS2 null mice, superoxide dismutase ( SOD ) was upregulated, and catalase and glutathione peroxidase 1 ( GPX 1) were downregulated, when compared to MAEC s from young and age‐matched wild‐type mice. Increased H 2 O 2 levels induced Fyn and extracellular signal‐regulated kinases ( ERK s) phosphorylation and K Ca 3.1 upregulation. Catalase/ GPX 1 double knockout (catalase −/− / GPX 1 −/− ) upregulated K Ca 3.1 in MAEC s. NO production was decreased in aged wild‐type, CerS2 null, and catalase −/− / GPX 1 −/− MAEC s. However, K Ca 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 −/− / GPX 1 −/− mice. CerS5 transfection or exogenous application of sphingosine or sphingosine 1‐phosphate induced similar changes in levels of the antioxidant enzymes and upregulated K Ca 3.1. Our findings suggest that, during aging‐related oxidative stress, SOD upregulation and downregulation of catalase and GPX 1, which occur upon altering the sphingolipid composition or acyl chain length, generate H 2 O 2 and thereby upregulate K Ca 3.1 expression and function via a H 2 O 2 /Fyn‐mediated pathway. Altogether, enhanced K Ca 3.1 activity may compensate for decreased NO signaling during vascular aging.