Cigarette Smoke Extract Inhibits Platelet Aggregation by Suppressing Cyclooxygenase Activity

Hitoshi Kashiwagi; Koh-ichi Yuhki; Yoshitaka Imamichi; Fumiaki Kojima; Shima Kumei; Tsunehito Higashi; Takahiro Horinouchi; Soichi Miwa; Shuh Narumiya; Fumitaka Ushikubi

doi:10.1055/s-0037-1607979

TH Open, Table of Contents

CC-BY 4.0 · TH Open 2017; 01(02): e122-e129
DOI: 10.1055/s-0037-1607979

Original Article

Georg Thieme Verlag KG Stuttgart · New York

Cigarette Smoke Extract Inhibits Platelet Aggregation by Suppressing Cyclooxygenase Activity

Hitoshi Kashiwagi

¹Department of Pharmacology, Asahikawa Medical University, Asahikawa, Japan

²Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo, Japan

,

Koh-ichi Yuhki

¹Department of Pharmacology, Asahikawa Medical University, Asahikawa, Japan

²Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo, Japan

,

Yoshitaka Imamichi

¹Department of Pharmacology, Asahikawa Medical University, Asahikawa, Japan

,

Fumiaki Kojima

²Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo, Japan

³Department of Pharmacology, Kitasato University, Sagamihara, Japan

,

Shima Kumei

¹Department of Pharmacology, Asahikawa Medical University, Asahikawa, Japan

²Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo, Japan

,

Tsunehito Higashi

⁴Department of Cellular Pharmacology, Hokkaido University Graduate School of Medicine, Sapporo, Japan

,

Takahiro Horinouchi

⁴Department of Cellular Pharmacology, Hokkaido University Graduate School of Medicine, Sapporo, Japan

,

Soichi Miwa

⁴Department of Cellular Pharmacology, Hokkaido University Graduate School of Medicine, Sapporo, Japan

,

Shuh Narumiya

²Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo, Japan

⁵Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan

,

Fumitaka Ushikubi

¹Department of Pharmacology, Asahikawa Medical University, Asahikawa, Japan

²Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo, Japan

› Author Affiliations

Abstract

The results of studies that were performed to determine whether cigarette smoking affects platelet function have been controversial, and the effects of nicotine- and tar-free cigarette smoke extract (CSE) on platelet function remain to be determined. The aim of this study was to determine the effect of CSE on platelet aggregation and to clarify the mechanism by which CSE affects platelet function. CSE inhibited murine platelet aggregation induced by 9,11-dideoxy-9α,11α-methanoepoxy-prosta-5Z,13E-dien-1-oic acid (U-46619), a thromboxane (TX) A₂ receptor agonist, and that induced by collagen with respective IC₅₀ values of 1.05 ± 0.14% and 1.34 ± 0.19%. A similar inhibitory action of CSE was also observed in human platelets. CSE inhibited arachidonic acid–induced TXA₂ production in murine platelets with an IC₅₀ value of 7.32 ± 2.00%. Accordingly, the inhibitory effect of CSE on collagen-induced aggregation was significantly blunted in platelets lacking the TXA₂ receptor compared with the inhibitory effect in control platelets. In contrast, the antiplatelet effects of CSE in platelets lacking each inhibitory prostanoid receptor, prostaglandin (PG) I₂ receptor and PGE₂ receptor subtypes EP₂ and EP₄, were not significantly different from the effects in respective control platelets. Among the enzymes responsible for TXA₂ production in platelets, the activity of cyclooxygenase (COX)-1 was inhibited by CSE with an IC₅₀ value of 1.07 ± 0.15% in an uncompetitive manner. In contrast, the activity of TX synthase was enhanced by CSE. The results indicate that CSE inhibits COX-1 activity and thereby decreases TXA₂ production in platelets, leading to inhibition of platelet aggregation.

Keywords

cigarette smoke extract - platelets - thromboxane A₂ - cyclooxygenase

Full Text

References

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