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

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. (c) 2022 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/ 4.0/).