Epoxyeicosatrienoic acids and the soluble epoxide hydrolase are determinants of pulmonary artery pressure and the acute hypoxic pulmonary vasoconstrictor response
Epoxyeicosatrienoic acids and the soluble epoxide hydrolase are determinants of pulmonary artery pressure and the acute hypoxic pulmonary vasoconstrictor response
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DOI：
10.1096/fj.08-112821
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发表时间：
2008-12-01
期刊：
影响因子：
4.8
通讯作者：
Fleming, Ingrid
中科院分区：
文献类型：
--
作者：
Keserue, Benjamin;Barbosa-Sicard, Eduardo;Fleming, Ingrid
最近的研究结果表明，细胞色素P-450（CYP）环氧合酶衍生的环氧二十碳三烯酸（Epoxyeicosatrienoic acids，ESTs）在急性缺氧性肺血管收缩（HPV）中的作用。考虑到EET的细胞内浓度由可溶性环氧化物水解酶（sEH）决定，我们评估了sEH和11，12-EET对离体小鼠肺中肺动脉压和HPV的影响。在野生型小鼠的肺中，通过sEH抑制，HPV显著增加，通过预先用β-环氧合酶抑制剂和EET拮抗剂14，15-EEZE消除这种作用。sEH（-/-）小鼠肺中HPV和EET的产生比野生型小鼠更大，sEH抑制对HPV没有进一步的影响，而MSPPOH和14，15-EEZE降低了反应。11，12-EET以浓度依赖性方式增加肺动脉压，并通过Rho依赖性机制增强HPV。11，12-EET和低氧均可诱导瞬时受体电位（TRP）C6-V5融合蛋白的膜转位，后者对14，15-EEZE敏感。此外，虽然急性缺氧和11，12-EET增加了TRPC 6（+/-）小鼠肺的肺压，但TRPC 6（-/-）小鼠的肺对这两种刺激均无反应。这些数据表明CYP衍生的EET参与HPV，并且在常氧和缺氧条件下EET诱导的肺收缩涉及TRPC 6依赖性途径。Keseru，B.，Barbosa-Sicard，E.，波普河，Fisslthaler，B.，Dietrich，A.，Gudermann，T.，吊床，B。D、法尔克，J. R.，Weissmann，N.，布塞河，巴西-地弗莱明岛环氧二十碳三烯酸和可溶性环氧化物水解酶是肺动脉压和急性缺氧性肺血管收缩反应的决定因素。FASEB J. 22，4306-4315（2008）
Recent findings have indicated a role for cytochrome P-450 (CYP) epoxygenase-derived epoxyeicosatrienoic acids (EETs) in acute hypoxic pulmonary vasoconstriction (HPV). Given that the intracellular concentration of EETs is determined by the soluble epoxide hydrolase (sEH), we assessed the influence of the sEH and 11,12-EET on pulmonary artery pressure and HPV in the isolated mouse lung. In lungs from wild-type mice, HPV was significantly increased by sEH inhibition, an effect abolished by pretreatment with CYP epoxygenase inhibitors and the EET antagonist 14,15-EEZE. HPV and EET production were greater in lungs from sEH(-/-) mice than from wild-type mice and sEH inhibition had no further effect on HPV, while MSPPOH and 14,15-EEZE decreased the response. 11,12-EET increased pulmonary artery pressure in a concentration-dependent manner and enhanced HPV via a Rho-dependent mechanism. Both 11,12-EET and hypoxia elicited the membrane translocation of a transient receptor potential (TRP) C6-V5 fusion protein, the latter effect was sensitive to 14,15-EEZE. Moreover, while acute hypoxia and 11,12-EET increased pulmonary pressure in lungs from TRPC6(+/-) mice, lungs from TRPC6(-/-) mice did not respond to either stimuli. These data demonstrate that CYP-derived EETs are involved in HPV and that EET-induced pulmonary contraction under normoxic and hypoxic conditions involves a TRPC6-dependent pathway.-Keseru, B., Barbosa-Sicard, E., Popp, R., Fisslthaler, B., Dietrich, A., Gudermann, T., Hammock, B. D., Falck, J. R., Weissmann, N., Busse, R., Fleming, I. Epoxyeicosatrienoic acids and the soluble epoxide hydrolase are determinants of pulmonary artery pressure and the acute hypoxic pulmonary vasoconstrictor response. FASEB J. 22, 4306-4315 (2008)