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- Publisher Website: 10.1093/cvr/cvu190
- Scopus: eid_2-s2.0-84913591514
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Article: Nitric oxide and protein kinase G act on TRPC1 to inhibit 11,12-EET-induced vascular relaxation
Title | Nitric oxide and protein kinase G act on TRPC1 to inhibit 11,12-EET-induced vascular relaxation |
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Authors | |
Keywords | Epoxyeicosatrienoic acids Nitric oxide TRP channels Vascular relaxation |
Issue Date | 2014 |
Citation | Cardiovascular Research, 2014, v. 104 n. 1, p. 138-146 How to Cite? |
Abstract | AIM: 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 Identifier | http://hdl.handle.net/10722/203520 |
ISSN | 2023 Impact Factor: 10.2 2023 SCImago Journal Rankings: 2.809 |
ISI Accession Number ID |
DC Field | Value | Language |
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dc.contributor.author | Zhang, P | en_US |
dc.contributor.author | Ma, Y | en_US |
dc.contributor.author | Wang, Y | en_US |
dc.contributor.author | Huang, Y | en_US |
dc.contributor.author | Li, RA | en_US |
dc.contributor.author | Yao, X | en_US |
dc.date.accessioned | 2014-09-19T15:23:23Z | - |
dc.date.available | 2014-09-19T15:23:23Z | - |
dc.date.issued | 2014 | en_US |
dc.identifier.citation | Cardiovascular Research, 2014, v. 104 n. 1, p. 138-146 | en_US |
dc.identifier.issn | 0008-6363 | - |
dc.identifier.uri | http://hdl.handle.net/10722/203520 | - |
dc.description.abstract | AIM: 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.language | eng | en_US |
dc.relation.ispartof | Cardiovascular Research | en_US |
dc.subject | Epoxyeicosatrienoic acids | - |
dc.subject | Nitric oxide | - |
dc.subject | TRP channels | - |
dc.subject | Vascular relaxation | - |
dc.title | Nitric oxide and protein kinase G act on TRPC1 to inhibit 11,12-EET-induced vascular relaxation | en_US |
dc.type | Article | en_US |
dc.identifier.email | Li, RA: ronaldli@hkucc.hku.hk | en_US |
dc.identifier.authority | Li, RA=rp01352 | en_US |
dc.identifier.doi | 10.1093/cvr/cvu190 | - |
dc.identifier.scopus | eid_2-s2.0-84913591514 | - |
dc.identifier.hkuros | 239619 | en_US |
dc.identifier.eissn | 1755-3245 | - |
dc.identifier.isi | WOS:000343317000015 | - |
dc.identifier.issnl | 0008-6363 | - |