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KCa 3.1上调可在衰老和氧化应激过程中维持内皮依赖性血管舒张。

KCa 3.1 upregulation preserves endothelium-dependent vasorelaxation during aging and oxidative stress.

作者信息

Choi Shinkyu, Kim Ji Aee, Li Hai-Yan, Shin Kyong-Oh, Oh Goo Taeg, Lee Yong-Moon, Oh Seikwan, Pewzner-Jung Yael, Futerman Anthony H, Suh Suk Hyo

机构信息

Department of Physiology, Medical School, Ewha Womans University, Seoul, South Korea.

College of Pharmacy and MRC, Chungbuk National University, Chongju, South Korea.

出版信息

Aging Cell. 2016 Oct;15(5):801-10. doi: 10.1111/acel.12502. Epub 2016 Jun 30.

DOI:10.1111/acel.12502
PMID:27363720
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5013018/
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.

摘要

内皮氧化应激随着衰老而发展，活性氧通过降低一氧化氮（NO）的可用性损害内皮依赖性舒张（EDR）。内皮KCa 3.1有助于EDR，其受H2O2上调。我们研究了在衰老相关的氧化应激过程中，KCa 3.1上调是否能补偿对NO的EDR减弱。先前的研究表明，在老年野生型和CerS2小鼠中，神经酰胺合酶5（CerS5）、鞘氨醇和鞘氨醇1-磷酸的水平升高。与来自年轻和年龄匹配的野生型小鼠的原代小鼠主动脉内皮细胞（MAECs）相比，来自老年野生型和CerS2基因敲除小鼠的MAECs中超氧化物歧化酶（SOD）上调，而过氧化氢酶和谷胱甘肽过氧化物酶1（GPX1）下调。H2O2水平升高诱导Fyn和细胞外信号调节激酶（ERKs）磷酸化以及KCa 3.1上调。过氧化氢酶/GPX1双敲除（catalase(-/-)/GPX1(-/-)）使MAECs中的KCa 3.1上调。老年野生型、CerS2基因敲除和catalase(-/-)/GPX1(-/-)的MAECs中NO生成减少。然而，在来自老年野生型、CerS2基因敲除和catalase(-/-)/GPX1(-/-)小鼠的主动脉环中，KCa 3.1激活诱导的、对N(G)-硝基-L-精氨酸和吲哚美辛耐药的EDR增加，而乙酰胆碱诱导的EDR没有变化。CerS5转染或外源性应用鞘氨醇或鞘氨醇1-磷酸诱导抗氧化酶水平发生类似变化并上调KCa 3.1。我们的研究结果表明，在衰老相关的氧化应激过程中，改变鞘脂组成或酰基链长度时发生的SOD上调以及过氧化氢酶和GPX1下调会产生H2O2，从而通过H2O2/Fyn介导的途径上调KCa 3.1的表达和功能。总之，增强的KCa 3.1活性可能补偿血管衰老过程中NO信号的降低。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b1fc/5013018/ddbc2966904b/ACEL-15-801-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b1fc/5013018/0a498ea66679/ACEL-15-801-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b1fc/5013018/8a642cb3223e/ACEL-15-801-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b1fc/5013018/821e50524732/ACEL-15-801-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b1fc/5013018/5904e1a120d9/ACEL-15-801-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b1fc/5013018/e303ba963722/ACEL-15-801-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b1fc/5013018/35c9cfad5351/ACEL-15-801-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b1fc/5013018/ddbc2966904b/ACEL-15-801-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b1fc/5013018/0a498ea66679/ACEL-15-801-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b1fc/5013018/8a642cb3223e/ACEL-15-801-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b1fc/5013018/821e50524732/ACEL-15-801-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b1fc/5013018/5904e1a120d9/ACEL-15-801-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b1fc/5013018/e303ba963722/ACEL-15-801-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b1fc/5013018/35c9cfad5351/ACEL-15-801-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b1fc/5013018/ddbc2966904b/ACEL-15-801-g007.jpg

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