Mutation of ARHGAP9 in patients with coronary spastic angina.
Coronary artery spasm has an important function in the etiology of variant angina and other acute coronary syndromes. Abnormal activation of Rho-family GTPases has been observed in cardiovascular disorders, but the function of genetic variability in Rho-family GTPases remains to be evaluated in cardiovascular disorders. We examined the genetic variability of Rho-family GTPases and their regulators in coronary artery spasm. We performed a comprehensive candidate gene analysis of 67 single nucleotide polymorphisms with amino-acid substitution in Rho-family GTPases and their regulators in 103 unrelated Japanese patients with acetylcholine-induced coronary artery spasm and 102 control Japanese subjects without acetylcholine-induced coronary artery spasm. We noted an association of the single nucleotide polymorphism of ARHGAP9 (rs11544238, Ala370Ser) with coronary artery spasm (odds ratio =2.67). We found that ARHGAP9 inactivated Rac as RacGAP and that the mRNA level of ARHGAP9 was strongly detected in hematopoietic cells. ARHGAP9 negatively regulated cell migration. The Ala370Ser polymorphism counteracted ARHGAP9-reduced cell migration, spreading and adhesion. The Ala370Ser polymorphism in the ARHGAP9 gene is associated with coronary artery spasm. These data suggest that the polymorphism of ARHGAP9 has a critical function in the infiltration of hematopoietic cells into the endothelium and inflammation leading to endothelial dysfunction.
Takefuji
Mikito
M
Department of Cell Pharmacology, Graduate School of Medicine, Nagoya University, 65 Tsurumai, Showa-ku, Nagoya, Japan.
Asano
Hiroyuki
H
Mori
Kazutaka
K
Amano
Mutsuki
M
Kato
Katsuhiro
K
Watanabe
Takashi
T
Morita
Yasuhiro
Y
Katsumi
Akira
A
Itoh
Toshiki
T
Takenawa
Tadaomi
T
Hirashiki
Akihiro
A
Izawa
Hideo
H
Nagata
Kozo
K
Hirayama
Haruo
H
Takatsu
Fumimaro
F
Naoe
Tomoki
T
Yokota
Mitsuhiro
M
Kaibuchi
Kozo
K
D000109:Acetylcholine / Q000008:administration & dosage; D000788:Angina Pectoris, Variant / Q000235:genetics / Q000503:physiopathology; D017023:Coronary Angiography; D003329:Coronary Vasospasm / Q000139:chemically induced / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics* / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006367:HeLa Cells; D006801:Humans; D007564:Japan; D019169:Jurkat Cells; D008297:Male; D009154:Mutation; D020641:Polymorphism, Single Nucleotide
C431580:ARHGAP9 protein, human; D020690:GTPase-Activating Proteins; D000109:Acetylcholine