Serotonin potentiates high-glucose-induced endothelial injury: the role of serotonin and 5-HT(2A) receptors in promoting thrombosis in diabetes.
To clarify the involvement of 5-hydroxytryptamine (5-HT) in promotion of thrombogenesis in diabetes, we examined the inhibitory effect of sarpogrelate, a 5-HT(2A) receptor antagonist, on thrombus formation in diabetic rats. In streptozotocin-induced diabetic rats, polyethylene tube-induced thrombus formation was enhanced compared with that in normal rats. The thrombogenesis was inhibited by sarpogrelate; cilostazol, a PDE3 inhibitor; and aspirin, a COX inhibitor, by 75.8%, 42.3%, and 34.3%, respectively. The inhibition by sarpogrelate was more pronounced in diabetic rats than normal ones. High glucose and 5-HT increased the expression of vascular cell adhesion molecule-1 (VCAM-1) in human umbilical vein endothelial cells (HUVECs) and combination of both high glucose and 5-HT further potentiated the effect. Sarpogrelate but not aspirin inhibited the increase in VCAM-1 expression induced by high glucose and 5-HT. These findings suggest that 5-HT mediates the enhanced thrombogenesis in diabetes and suggests that a 5-HT(2A) receptor antagonist may have novel therapeutic potential for the treatment of diabetic complications.
Pharmacology Research Laboratories I, Research Division, Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan.
Kumi
K
Yamada
Hisae
H
Niki
Hitoshi
H
Nagai
Masakuni
M
Nishikawa
Haruto
H
Nakagawa
D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D002478:Cells, Cultured; D000077407:Cilostazol; D003921:Diabetes Mellitus, Experimental / Q000097:blood* / Q000378:metabolism / Q000473:pathology; D005343:Fibrinolytic Agents / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism* / Q000494:pharmacology*; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000494:pharmacology; D013386:Succinates / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology; D013927:Thrombosis / Q000188:drug therapy* / Q000378:metabolism / Q000517:prevention & control; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D005343:Fibrinolytic Agents; D044402:Receptor, Serotonin, 5-HT2A; D058830:Serotonin 5-HT2 Receptor Antagonists; D013386:Succinates; D013777:Tetrazoles; D019010:Vascular Cell Adhesion Molecule-1; C064294:sarpogrelate; D012701:Serotonin; D005947:Glucose; D000077407:Cilostazol; D001241:Aspirin