Cilostazol Suppresses Angiotensin II–Induced Vasoconstriction via Protein Kinase A–Mediated Phosphorylation of the Transient Receptor Potential Canonical 6 Channel
Autor: | Hitoshi Kurose, Takahiro Iwamoto, Mayumi Hirano, Ryuji Inoue, Michio Nakaya, Zhong Jian, Shota Saiki, Motohiro Nishida, Yoji Sato, Satomi Kita, Marina Ariyoshi, Kinue Nishioka, Katsuya Hirano |
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Rok vydání: | 2011 |
Předmět: |
Male
rho GTP-Binding Proteins medicine.medical_specialty Vasodilator Agents Myocytes Smooth Muscle Phosphodiesterase 3 Tetrazoles Aorta Thoracic Phosphodiesterase 3 Inhibitors Transfection Muscle Smooth Vascular TRPC6 Diglycerides Rats Sprague-Dawley Mice Transient receptor potential channel TRPC3 Internal medicine TRPC6 Cation Channel medicine Animals Humans Vasoconstrictor Agents Calcium Signaling Phosphorylation Protein kinase A TRPC TRPC Cation Channels Dose-Response Relationship Drug Chemistry Angiotensin II Cyclic AMP-Dependent Protein Kinases Cilostazol Rats Cell biology HEK293 Cells Endocrinology Vasoconstriction Mutation Cardiology and Cardiovascular Medicine Protein Processing Post-Translational |
Zdroj: | Arteriosclerosis, Thrombosis, and Vascular Biology. 31:2278-2286 |
ISSN: | 1524-4636 1079-5642 |
Popis: | Objective— The goal of this study was to determine whether inhibition of transient receptor potential canonical (TRPC) channels underlies attenuation of angiotensin II (Ang II)–induced vasoconstriction by phosphodiesterase (PDE) 3 inhibition. Methods and Results— Pretreatment of rat thoracic aorta with cilostazol, a selective PDE3 inhibitor, suppressed vasoconstriction induced by Ang II but not that induced by KCl. The Ang II–induced contraction was largely dependent on Ca 2+ influx via receptor-operated cation channels. Cilostazol specifically suppressed diacylglycerol-activated TRPC channels (TRPC3/TRPC6/TRPC7) through protein kinase A (PKA)–dependent phosphorylation of TRPC channels in HEK293 cells. In contrast, we found that phosphorylation of TRPC6 at Thr69 was essential for the suppression of Ang II–induced Ca 2+ influx by PDE3 inhibition in rat aortic smooth muscle cells (RAoSMCs). Cilostazol specifically induced phosphorylation of endogenous TRPC6 at Thr69. The endogenous TRPC6, but not TRPC3, formed a ternary complex with PDE3 and PKA in RAoSMCs, suggesting the specificity of TRPC6 phosphorylation by PDE3 inhibition. Furthermore, inhibition of PDE3 suppressed the Ang II–induced contraction of reconstituted ring with RAoSMCs, which were abolished by the expression of a phosphorylation-deficient mutant of TRPC6. Conclusion— PKA-mediated phosphorylation of TRPC6 at Thr69 is essential for the vasorelaxant effects of PDE3 inhibition against the vasoconstrictive actions of Ang II. |
Databáze: | OpenAIRE |
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