PMID- 27363720
OWN - NLM
STAT- MEDLINE
DCOM- 20170605
LR  - 20181113
IS  - 1474-9726 (Electronic)
IS  - 1474-9718 (Print)
IS  - 1474-9718 (Linking)
VI  - 15
IP  - 5
DP  - 2016 Oct
TI  - KCa 3.1 upregulation preserves endothelium-dependent vasorelaxation during aging 
      and oxidative stress.
PG  - 801-10
LID - 10.1111/acel.12502 [doi]
AB  - 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.
CI  - (c) 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley 
      & Sons Ltd.
FAU - Choi, Shinkyu
AU  - Choi S
AD  - Department of Physiology, Medical School, Ewha Womans University, Seoul, South 
      Korea.
FAU - Kim, Ji Aee
AU  - Kim JA
AD  - Department of Physiology, Medical School, Ewha Womans University, Seoul, South 
      Korea.
FAU - Li, Hai-Yan
AU  - Li HY
AD  - Department of Physiology, Medical School, Ewha Womans University, Seoul, South 
      Korea.
FAU - Shin, Kyong-Oh
AU  - Shin KO
AD  - College of Pharmacy and MRC, Chungbuk National University, Chongju, South Korea.
FAU - Oh, Goo Taeg
AU  - Oh GT
AD  - Department of Life Sciences, Ewha Womans University, Seoul, South Korea.
FAU - Lee, Yong-Moon
AU  - Lee YM
AD  - College of Pharmacy and MRC, Chungbuk National University, Chongju, South Korea.
FAU - Oh, Seikwan
AU  - Oh S
AD  - Department of Molecular Medicine, Medical School, Ewha Womans University, Seoul, 
      South Korea.
FAU - Pewzner-Jung, Yael
AU  - Pewzner-Jung Y
AD  - Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, 
      Israel.
FAU - Futerman, Anthony H
AU  - Futerman AH
AD  - Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, 
      Israel.
FAU - Suh, Suk Hyo
AU  - Suh SH
AD  - Department of Physiology, Medical School, Ewha Womans University, Seoul, South 
      Korea.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20160630
PL  - England
TA  - Aging Cell
JT  - Aging cell
JID - 101130839
RN  - 0 (Antioxidants)
RN  - 0 (Intermediate-Conductance Calcium-Activated Potassium Channels)
RN  - 0 (Kcnn4 protein, mouse)
RN  - 0 (Sphingolipids)
RN  - 2149-70-4 (Nitroarginine)
RN  - BBX060AN9V (Hydrogen Peroxide)
RN  - EC 1.- (Oxidoreductases)
RN  - EC 1.3.1.- (dihydroceramide desaturase)
RN  - EC 2.7.10.2 (Fyn protein, mouse)
RN  - EC 2.7.10.2 (Proto-Oncogene Proteins c-fyn)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
RN  - XXE1CET956 (Indomethacin)
SB  - IM
MH  - Aging/drug effects/*physiology
MH  - Animals
MH  - Antioxidants/metabolism
MH  - Aorta/pathology
MH  - Endothelial Cells/metabolism/pathology
MH  - Endothelium, Vascular/drug effects/*physiology
MH  - Enzyme Activation/drug effects
MH  - Extracellular Signal-Regulated MAP Kinases/metabolism
MH  - Hydrogen Peroxide/metabolism
MH  - Indomethacin/pharmacology
MH  - Intermediate-Conductance Calcium-Activated Potassium Channels/*metabolism
MH  - Ion Channel Gating/drug effects
MH  - Mice, Knockout
MH  - Models, Biological
MH  - Nitroarginine/pharmacology
MH  - Oxidative Stress/*drug effects
MH  - Oxidoreductases/deficiency/metabolism
MH  - Proto-Oncogene Proteins c-fyn/metabolism
MH  - Sphingolipids/metabolism
MH  - *Up-Regulation/drug effects
MH  - *Vasodilation/drug effects
PMC - PMC5013018
OTO - NOTNLM
OT  - Ca2+-activated K+ channel
OT  - aging
OT  - ceramide synthase 2 ablation
OT  - endothelial cells
OT  - oxidative stress
OT  - redox enzymes
EDAT- 2016/07/02 06:00
MHDA- 2017/06/06 06:00
PMCR- 2016/10/01
CRDT- 2016/07/02 06:00
PHST- 2016/03/17 00:00 [accepted]
PHST- 2016/07/02 06:00 [entrez]
PHST- 2016/07/02 06:00 [pubmed]
PHST- 2017/06/06 06:00 [medline]
PHST- 2016/10/01 00:00 [pmc-release]
AID - ACEL12502 [pii]
AID - 10.1111/acel.12502 [doi]
PST - ppublish
SO  - Aging Cell. 2016 Oct;15(5):801-10. doi: 10.1111/acel.12502. Epub 2016 Jun 30.