Cilostazol suppresses angiotensin II-induced vasoconstriction via protein kinase A-mediated phosphorylation of the transient receptor potential canonical 6 channel

Kinue Nishioka, Motohiro Nishida, Marina Ariyoshi, Zhong Jian, Shota Saiki, Mayumi Hirano, Nakaya Michio, Yoji Sato, Satomi Kita, Takahiro Iwamoto, Katsuya Hirano, Ryuji Inoue, Hitoshi Kurose

Research output: Contribution to journalArticle

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Abstract

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 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 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.

Original languageEnglish
Pages (from-to)2278-2286
Number of pages9
JournalArteriosclerosis, thrombosis, and vascular biology
Volume31
Issue number10
DOIs
Publication statusPublished - Oct 1 2011

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Cyclic AMP-Dependent Protein Kinases
Vasoconstriction
Angiotensin II
Phosphorylation
Transient Receptor Potential Channels
Smooth Muscle Myocytes
Phosphodiesterase 3 Inhibitors
HEK293 Cells
Diglycerides
Phosphoric Diester Hydrolases
Thoracic Aorta
Vasodilator Agents
cilostazol
Cations

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

Cite this

Cilostazol suppresses angiotensin II-induced vasoconstriction via protein kinase A-mediated phosphorylation of the transient receptor potential canonical 6 channel. / Nishioka, Kinue; Nishida, Motohiro; Ariyoshi, Marina; Jian, Zhong; Saiki, Shota; Hirano, Mayumi; Michio, Nakaya; Sato, Yoji; Kita, Satomi; Iwamoto, Takahiro; Hirano, Katsuya; Inoue, Ryuji; Kurose, Hitoshi.

In: Arteriosclerosis, thrombosis, and vascular biology, Vol. 31, No. 10, 01.10.2011, p. 2278-2286.

Research output: Contribution to journalArticle

Nishioka, Kinue ; Nishida, Motohiro ; Ariyoshi, Marina ; Jian, Zhong ; Saiki, Shota ; Hirano, Mayumi ; Michio, Nakaya ; Sato, Yoji ; Kita, Satomi ; Iwamoto, Takahiro ; Hirano, Katsuya ; Inoue, Ryuji ; Kurose, Hitoshi. / Cilostazol suppresses angiotensin II-induced vasoconstriction via protein kinase A-mediated phosphorylation of the transient receptor potential canonical 6 channel. In: Arteriosclerosis, thrombosis, and vascular biology. 2011 ; Vol. 31, No. 10. pp. 2278-2286.
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T1 - Cilostazol suppresses angiotensin II-induced vasoconstriction via protein kinase A-mediated phosphorylation of the transient receptor potential canonical 6 channel

AU - Nishioka, Kinue

AU - Nishida, Motohiro

AU - Ariyoshi, Marina

AU - Jian, Zhong

AU - Saiki, Shota

AU - Hirano, Mayumi

AU - Michio, Nakaya

AU - Sato, Yoji

AU - Kita, Satomi

AU - Iwamoto, Takahiro

AU - Hirano, Katsuya

AU - Inoue, Ryuji

AU - Kurose, Hitoshi

PY - 2011/10/1

Y1 - 2011/10/1

N2 - 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 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 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.

AB - 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 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 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.

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JO - Arteriosclerosis, Thrombosis, and Vascular Biology

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