Aspirin inhibits thrombin action on endothelial cells via up-regulation of aminopeptidase N/CD13 expression.
OBJECTIVE
We hypothesized that aspirin may exhibit its anti-atherosclerotic effects via mechanisms other than cyclooxygenase inhibition in platelets.


RESULTS
Using enhanced subtraction hybridization analysis, we found in human umbilical vein endothelial cells (HUVECs) that aspirin up-regulates the expression of aminopeptidase N (APN/CD13) mRNA and its surface protein levels in a dose-dependent manner. Enzymatic activity of APN/CD13 on HUVECs was increased approximately 1.5-fold by 1 mmol L(-1) of aspirin, and treatment with bestatin, an inhibitor for APN/CD13 metalloprotease activity, attenuated the enhanced activities of APN/CD13. Since activated thrombin receptor is reported to be inactivated by APN/CD13 in vitro, protective actions of aspirin on HUVECs by thrombin stimulation were examined, resulting in the suppression of endothelin-1 and reactive oxygen species productions in HUVECs. These inhibitory actions of aspirin were partially abrogated by bestatin.


CONCLUSIONS
Aspirin may exert its anti-atherothrombotic effects in part via the inhibition of thrombin action by up-regulating APN/CD13 on endothelial cells.
Kato
Midori
M
Department of Medicine and Bioregulatory Sciences, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
Azuma
Hiroyuki
H
Akaike
Masashi
M
Iuchi
Takahiko
T
Aihara
Ken-ichi
K
Ikeda
Yasumasa
Y
Fujimura
Mitsunori
M
Yoshida
Tomonori
T
Yamaguchi
Hiroshi
H
Hashizume
Shunji
S
Matsumoto
Toshio
T
D001241:Aspirin / Q000494:pharmacology*; D018826:CD13 Antigens / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured / Q000187:drug effects / Q000201:enzymology; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology; D019332:Endothelin-1 / Q000096:biosynthesis / Q000235:genetics; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology; D004790:Enzyme Induction / Q000187:drug effects; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D017930:Genes, Reporter; D006801:Humans; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D017382:Reactive Oxygen Species / Q000378:metabolism; D013382:Subtraction Technique; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D014471:Umbilical Veins
D019332:Endothelin-1; D005343:Fibrinolytic Agents; D011480:Protease Inhibitors; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D018826:CD13 Antigens; D013917:Thrombin; D007930:Leucine; C012211:ubenimex; D001241:Aspirin