Quinonoid dihydropteridine reductase, a tetrahydrobiopterin-recycling enzyme, contributes to 5-hydroxytryptamine-associated platelet aggregation in mice

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Abstract

Quinonoid dihydropteridine reductase (QDPR) regenerates tetrahydrobiopterin (BH4), which is an essential cofactor for catecholamine and serotonin (5-hydroxytryptamine, 5-HT) biosynthesis. Serotonin is known as an important platelet agonist, but its role under BH4-synthesizing or recycling enzymes deficiency is unknown. In the present study, we evaluated the effect of Qdpr gene disruption on platelet aggregation using knockout (Qdpr−/−) mice. Platelet aggregation was monitored by light transmission aggregometry using adenosine diphosphate (ADP) and collagen as agonists. We also assessed how platelet aggregation was modified by 5-HT recovery through supplementation with 5-hydroxytryptophan (5-HTP), a 5-HT precursor, or by blocking the serotonin 5-HT2A receptor. Platelet aggregation in the Qdpr−/− mice was significantly suppressed in comparison with that in wild-type (Qdpr+/+) mice, particularly at the maintenance phase of aggregation. 5-HT storage was decreased in Qdpr−/− platelets, and 5-HTP supplementation recovered not only the intraplatelet 5-HT levels but also platelet aggregation. In addition, 5-HT signal blockade using sarpogrelate suppressed platelet aggregation in Qdpr+/+ mice, and platelets in Qdpr−/− mice were hardly affected. Our results indicate that QDPR deficiency suppresses platelet aggregation by impairing 5-HT biosynthesis in mice.

Original languageEnglish
Pages (from-to)173-179
Number of pages7
JournalJournal of Pharmacological Sciences
Volume150
Issue number3
DOIs
Publication statusPublished - 11-2022

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

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