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Article: Nitric oxide and protein kinase G act on TRPC1 to inhibit 11,12-EET-induced vascular relaxation

TitleNitric oxide and protein kinase G act on TRPC1 to inhibit 11,12-EET-induced vascular relaxation
Authors
Issue Date2014
Citation
Cardiovascular Research, 2014, v. 104 n. 1, p. 138-146 How to Cite?
AbstractAIM: Vascular endothelial cells synthesize and release vasodilators such as nitric oxide (NO) and epoxyeicosatrienoic acids (EETs). NO is known to inhibit EET-induced smooth muscle hyperpolarization and relaxation. This study investigates the underlying mechanism of this inhibition. METHODS AND RESULTS: Through measurements of membrane potential and arterial tension, we show that 11,12-EET induced membrane hyperpolarization and vascular relaxation in endothelium-denuded porcine coronary arteries. These responses were suppressed by S-nitroso-N-acetylpenicillamine (SNAP) and 8-Br-cGMP, an NO donor and a membrane-permeant analogue of cGMP, respectively. The inhibitory actions of SNAP and 8-Br-cGMP on 11,12-EET-induced membrane hyperpolarization and vascular relaxation were reversed by hydroxocobalamin, an NO scavenger; ODQ, a guanylyl cyclase inhibitor; and KT5823, a protein kinase G (PKG) inhibitor. The inhibitory actions of SNAP and 8-bromo cyclic GMP (8-Br-cGMP) on the EET responses were also abrogated by shielding TRPC1-PKG phosphorylation sites with an excessive supply of exogenous PKG substrates, TAT-TRPC1S172 and TAT-TRPC1T313. Furthermore, a phosphorylation assay demonstrated that PKG could directly phosphorylate TRPC1 at Ser172 and Thr313. In addition, 11,12-EET failed to induce membrane hyperpolarization and vascular relaxation when TRPV4, TRPC1, or KCa1.1 was selectively inhibited. Co-immunoprecipitation studies demonstrated that TRPV4, TRPC1, and KCa1.1 physically associated with each other in smooth muscle cells. CONCLUSION: Our findings demonstrate a novel role of the NO-cGMP-PKG pathway in the inhibition of 11,12-EET-induced smooth muscle hyperpolarization and relaxation via PKG-mediated phosphorylation of TRPC1.
Persistent Identifierhttp://hdl.handle.net/10722/203520

 

DC FieldValueLanguage
dc.contributor.authorZhang, Pen_US
dc.contributor.authorMa, Yen_US
dc.contributor.authorWang, Yen_US
dc.contributor.authorHuang, Yen_US
dc.contributor.authorLi, RAen_US
dc.contributor.authorYao, Xen_US
dc.date.accessioned2014-09-19T15:23:23Z-
dc.date.available2014-09-19T15:23:23Z-
dc.date.issued2014en_US
dc.identifier.citationCardiovascular Research, 2014, v. 104 n. 1, p. 138-146en_US
dc.identifier.urihttp://hdl.handle.net/10722/203520-
dc.description.abstractAIM: Vascular endothelial cells synthesize and release vasodilators such as nitric oxide (NO) and epoxyeicosatrienoic acids (EETs). NO is known to inhibit EET-induced smooth muscle hyperpolarization and relaxation. This study investigates the underlying mechanism of this inhibition. METHODS AND RESULTS: Through measurements of membrane potential and arterial tension, we show that 11,12-EET induced membrane hyperpolarization and vascular relaxation in endothelium-denuded porcine coronary arteries. These responses were suppressed by S-nitroso-N-acetylpenicillamine (SNAP) and 8-Br-cGMP, an NO donor and a membrane-permeant analogue of cGMP, respectively. The inhibitory actions of SNAP and 8-Br-cGMP on 11,12-EET-induced membrane hyperpolarization and vascular relaxation were reversed by hydroxocobalamin, an NO scavenger; ODQ, a guanylyl cyclase inhibitor; and KT5823, a protein kinase G (PKG) inhibitor. The inhibitory actions of SNAP and 8-bromo cyclic GMP (8-Br-cGMP) on the EET responses were also abrogated by shielding TRPC1-PKG phosphorylation sites with an excessive supply of exogenous PKG substrates, TAT-TRPC1S172 and TAT-TRPC1T313. Furthermore, a phosphorylation assay demonstrated that PKG could directly phosphorylate TRPC1 at Ser172 and Thr313. In addition, 11,12-EET failed to induce membrane hyperpolarization and vascular relaxation when TRPV4, TRPC1, or KCa1.1 was selectively inhibited. Co-immunoprecipitation studies demonstrated that TRPV4, TRPC1, and KCa1.1 physically associated with each other in smooth muscle cells. CONCLUSION: Our findings demonstrate a novel role of the NO-cGMP-PKG pathway in the inhibition of 11,12-EET-induced smooth muscle hyperpolarization and relaxation via PKG-mediated phosphorylation of TRPC1.en_US
dc.languageengen_US
dc.relation.ispartofCardiovascular Researchen_US
dc.titleNitric oxide and protein kinase G act on TRPC1 to inhibit 11,12-EET-induced vascular relaxationen_US
dc.typeArticleen_US
dc.identifier.emailLi, RA: ronaldli@hkucc.hku.hken_US
dc.identifier.authorityLi, RA=rp01352en_US
dc.identifier.doi10.1093/cvr/cvu190-
dc.identifier.hkuros239619en_US

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