title: Coronary vasospasm induced in transgenic mouse with increased phospholipase C-δ1 activity.
abstract: BACKGROUND
  We reported that phospholipase C (PLC)-δ1 activity was enhanced 3-fold in patients with coronary spastic angina. We detected variant PLC-δ1 with replacement of arginine 257 by histidine (R257H) showing increased enzymatic activity. We tested the hypothesis that increased PLC-δ1 activity causes enhanced coronary vasomotility.
  
  
  RESULTS
  We generated transgenic (TG) mice with human R257H variant PLC-δ1 in vascular smooth muscle cells. PLC enzymatic activity in the coronary artery was increased by 2.57 and 1.89 times, respectively, in homozygous and heterozygous TG compared with wild-type (WT) mice. ST elevation after ergometrine occurred in 17 of 18 homozygous TG, 6 of 20 heterozygous TG, and 3 of 22 WT mice (P<0.01, homozygous TG versus WT; P<0.05, homozygous TG versus heterozygous TG; P=NS, heterozygous TG versus WT). ST elevation was associated with bradyarrhythmias in homozygous TG mice. Focal coronary artery narrowing was documented with the microvascular filling technique in 3 of 5 homozygous TG mice after ergometrine but not in any of 7 WT mice (P<0.05). In the isolated Langendorff hearts, coronary perfusion pressure was increased after ergometrine in homozygous TG mice (P<0.01) but not in heterozygous TG or WT mice. Coronary perfusion pressure increase after prostaglandin F2α was similar among homozygous TG, heterozygous TG, and WT mice. Cultured rat aortic smooth muscle cells transfected with variant PLC-δ1 showed a higher PLC activity than those with WT PLC-δ1 (P<0.05) and furthermore showed greater intracellular Ca2+ response to acetylcholine in variant than in WT PLC-δ1 (P<0.05).
  
  
  CONCLUSIONS
  Increased PLC-δ1 activity enhances coronary vasomotility such as that seen in patients with coronary spastic angina.
authors.affiliation: Department of Cardiology, Hirosaki University Graduate School of Medicine, 5 Zaifu-Cho, Hirosaki, 036-8562 Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Shibutani
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Osanai
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Ashitate
authors.forename: Shigeki
authors.initials: S
authors.lastname: Sagara
authors.forename: Kei
authors.initials: K
authors.lastname: Izumiyama
authors.forename: Yuko
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Kenji
authors.initials: K
authors.lastname: Hanada
authors.forename: Takashi
authors.initials: T
authors.lastname: Echizen
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Tomita
authors.forename: Takeshi
authors.initials: T
authors.lastname: Fujita
authors.forename: Takeshi
authors.initials: T
authors.lastname: Miwa
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Matsubara
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Homma
authors.forename: Ken
authors.initials: K
authors.lastname: Okumura
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003326:Coronary Circulation / Q000235:genetics; D003329:Coronary Vasospasm / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D004790:Enzyme Induction / Q000235:genetics; D014644:Genetic Variation / Q000502:physiology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D054803:Phospholipase C delta / Q000096:biosynthesis / Q000235:genetics*; D051381:Rats; D015854:Up-Regulation / Q000235:genetics
chemical_list: D054803:Phospholipase C delta; C518025:Plcd1 protein, mouse