C-Src, ERK1/2 and Rho kinase mediate hydrogen peroxide-induced vascular contraction in hypertension. Issue 1 (January 2015)

• Record Type: Journal Article
• Authors: García-Redondo, Ana B.; Briones, Ana M.; Martínez-Revelles, Sonia; Palao, Teresa; Vila, Luis; Alonso, María J.; Salaices, Mercedes
• Is Part Of: Journal of hypertension. Volume 33:Issue 1(2015:Jan.)
• Publication Date: 2015-01
• Subjects: Hypertension -- Periodicals; Hypertension -- Periodicals; 616.132005
• DOI: 10.1097/HJH.0000000000000383
• Languages: English
• ISSNs: 1473-5598

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <title>Aim:</title> <p>The aim of this study was to analyse the signalling pathways involved in H<sub>2</sub>O<sub>2</sub> vascular responses in hypertension.</p> </sec> <sec> <title>Methods:</title> <p>Vascular function, thromboxane A<sub>2</sub> (TXA<sub>2</sub>) production, oxidative stress and protein expression were determined in mesenteric resistance arteries (MRAs) from hypertensive (spontaneously hypertensive rats, SHR) and normotensive Wistar Kyoto (WKY) rats.</p> </sec> <sec> <title>Results:</title> <p>H<sub>2</sub>O<sub>2</sub> and the TP agonist U46619 induced greater contractile responses in MRA from SHR than WKY. Moreover, H<sub>2</sub>O<sub>2</sub> increased TXA<sub>2</sub> production more in SHR than in WKY. The c-Src inhibitor PP1 reduced H<sub>2</sub>O<sub>2</sub> and U46619-induced contraction and TXA<sub>2</sub> release in both strains. The ERK1/2 inhibitor PD98059 reduced H<sub>2</sub>O<sub>2</sub> but not U46619-induced contraction only in SHR arteries. The Rho kinase inhibitor Y26372 reduced H<sub>2</sub>O<sub>2</sub> and U46619-induced contractions only in SHR arteries. Basal c-Src, ERK1/2 and Rho kinase expression were greater in MRA from SHR than WKY. In SHR, the combination of PD98059 with the TP antagonist SQ29548 but not with Y27632 inhibited the H<sub>2</sub>O<sub>2</sub> contraction more than each inhibitor alone. H<sub>2</sub>O<sub>2</sub> and U46619 increased NAD(P)H oxidase activity and O<sub>2</sub><sup>.-</sup> production and decreased mitochondrial membrane potential in vessels from SHR. The effects induced by H<sub>2</sub>O<sub>2</sub> were abolished by inhibitors of TXA<sub>2</sub> synthase, ERK1/2 and c-Src. The mitochondrial antioxidant mitoTEMPO reduced H<sub>2</sub>O<sub>2</sub>-induced contraction and NAD(P)H oxidase activation.</p> </sec> <sec> <title>Conclusion:</title> <p>In arteries from WKY, c-Src mediates H<sub>2</sub>O<sub>2</sub> contractile responses by modulating TXA<sub>2</sub> release and TXA<sub>2</sub> effect. In SHR, H<sub>2</sub>O<sub>2</sub> induces c-Src dependent TXA<sub>2</sub> release that provokes vascular contractile responses through Rho kinase, c-Src and O<sub>2</sub><sup>.-</sup> from NAD(P)H Oxidase and mitochondria. Moreover, ERK1/2 activation contributes to H<sub>2</sub>O<sub>2</sub> contraction in SHR through effects on mitochondria/NAD(P)H Oxidase.</p> </sec> </abstract>