Wall stretch and thromboxane A(2) activate NO synthase (eNOS) in pulmonary arterial smooth muscle cells via H2O2 and Akt-dependent phosphorylation
- Authors
- Kim, Hae Jin; Yoo, Hae Young; Jang, Ji Hyun; Lin, Hai Yue; Seo, Eun Yeong; Zhang, Yin Hua; Kim, Sung Joon
- Issue Date
- Apr-2016
- Publisher
- SPRINGER
- Keywords
- Pulmonary artery smooth muscle; Endothelial NO synthase; Stretch; Hydrogen peroxide
- Citation
- PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY, v.468, no.4, pp 705 - 716
- Pages
- 12
- Journal Title
- PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY
- Volume
- 468
- Number
- 4
- Start Page
- 705
- End Page
- 716
- URI
- https://scholarworks.bwise.kr/cau/handle/2019.sw.cau/7062
- DOI
- 10.1007/s00424-015-1778-1
- ISSN
- 0031-6768
1432-2013
- Abstract
- Pulmonary arteries (PAs) have high compliance, buffering the wide ranges of blood flow. Here, we addressed a hypothesis that PA smooth muscle cells (PASMCs) express nitric oxide synthases (NOS) that might be activated by mechanical stress and vasoactive agonists. In the myograph study of endothelium-denuded rat PAs, NOS inhibition (L-NAME) induced strong contraction (96 % of 80 mM KCl-induced contraction (80K)) in the presence of 5 nM U46619 (thromboxane A(2) (TXA(2)) analogue) with relatively high basal stretch (2.94 mN, S(+)). With lower basal stretch (0.98 mN, S(-)), however, L-NAME application following U46619 (TXA(2)/L-NAME) induced weak contraction (27 % of 80K). Inhibitors of nNOS and iNOS had no such effect in S(+) PAs. In endothelium-denuded S(+) mesenteric and renal arteries, TXA(2)/L-NAME-induced contraction was only 18 and 21 % of 80K, respectively. Expression of endothelial-type NOS (eNOS) in rat PASMCs was confirmed by RT-PCR and immunohistochemistry. Even in S(-) PAs, pretreatment with H2O2 (0.1-10 mu M) effectively increased the sensitivity to TXA(2)/L-NAME (105 % of 80K). Vice versa, NADPH oxidase inhibitors, reactive oxygen species scavengers, or an Akt inhibitor (SC-66) suppressed TXA(2)/L-NAME-induced contraction in S(+) PAs. In a human PASMC line, immunoblot analysis showed the following: (1) eNOS expression, (2) Ser(1177) phosphorylation by U46619 and H2O2, and (3) Akt activation (Ser(473) phosphorylation) by U46619. In the cell-attached patch clamp study, H2O2 facilitated membrane stretch-activated cation channels in rat PASMCs. Taken together, the muscular eNOS in PAs can be activated by TXA(2) and mechanical stress via H2O2 and Akt-mediated signaling, which may counterbalance the contractile signals from TXA(2) and mechanical stimuli.
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