title: Enhanced p122RhoGAP/DLC-1 Expression Can Be a Cause of Coronary Spasm.
abstract: BACKGROUND
  We previously showed that phospholipase C (PLC)-δ1 activity was enhanced by 3-fold in patients with coronary spastic angina (CSA). We also reported that p122Rho GTPase-activating protein/deleted in liver cancer-1 (p122RhoGAP/DLC-1) protein, which was discovered as a PLC-δ1 stimulator, was upregulated in CSA patients. We tested the hypothesis that p122RhoGAP/DLC-1 overexpression causes coronary spasm.
  
  
  RESULTS
  We generated transgenic (TG) mice with vascular smooth muscle (VSM)-specific overexpression of p122RhoGAP/DLC-1. The gene and protein expressions of p122RhoGAP/DLC-1 were markedly increased in the aorta of homozygous TG mice. Stronger staining with anti-p122RhoGAP/DLC-1 in the coronary artery was found in TG than in WT mice. PLC activities in the plasma membrane fraction and the whole cell were enhanced by 1.43 and 2.38 times, respectively, in cultured aortic vascular smooth muscle cells from homozygous TG compared with those from WT mice. Immediately after ergometrine injection, ST-segment elevation was observed in 1 of 7 WT (14%), 6 of 7 heterozygous TG (84%), and 7 of 7 homozygous TG mice (100%) (p<0.05, WT versus TGs). In the isolated Langendorff hearts, coronary perfusion pressure was increased after ergometrine in TG, but not in WT mice, despite of the similar response to prostaglandin F2α between TG and WT mice (n = 5). Focal narrowing of the coronary artery after ergometrine was documented only in TG mice.
  
  
  CONCLUSIONS
  VSM-specific overexpression of p122RhoGAP/DLC-1 enhanced coronary vasomotility after ergometrine injection in mice, which is relevant to human CSA.
authors.affiliation: Department of Cardiology and Nephrology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Kinjo
authors.affiliation: Department of Hypertension and Stroke Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: Department of Health Promotion, Hirosaki University Graduate School of Health Science, Hirosaki, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Osanai
authors.affiliation: Department of Cardiology and Nephrology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Shibutani
authors.affiliation: Department of Cardiology and Nephrology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Ikuyo
authors.initials: I
authors.lastname: Narita
authors.affiliation: Department of Cardiology and Nephrology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Tanno
authors.affiliation: Department of Cardiology and Nephrology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Kimitaka
authors.initials: K
authors.lastname: Nishizaki
authors.affiliation: Department of Cardiology and Nephrology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ichikawa
authors.affiliation: Department of Cardiology and Nephrology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kimura
authors.affiliation: Department of Cardiology and Nephrology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ishida
authors.affiliation: Department of Cardiology and Nephrology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yokota
authors.affiliation: Department of Cardiology and Nephrology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Michiko
authors.initials: M
authors.lastname: Shimada
authors.affiliation: Department of Biomolecular Science, Fukushima Medical University School of Medicine, Fukushima, Japan.
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Homma
authors.affiliation: Department of Cardiology and Nephrology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Tomita
authors.affiliation: Department of Cardiology and Nephrology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.|Department of Hypertension and Stroke Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Okumura
mesh_terms: D000787:Angina Pectoris / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D003329:Coronary Vasospasm / Q000378:metabolism*; D003331:Coronary Vessels / Q000378:metabolism*; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology
chemical_list: C430864:DLC-1 (deleted in liver cancer) protein, mouse; D020690:GTPase-Activating Proteins; D025521:Tumor Suppressor Proteins