Coronary Vasospasm Induced in Transgenic Mouse With Increased Phospholipase C-δ1 Activity

Background-We reported that phospholipase C (PLC)-delta 1 activity was enhanced 3-fold in patients with coronary spastic angina. We detected variant PLC-delta 1 with replacement of arginine 257 by histidine (R257H) showing increased enzymatic activity. We tested the hypothesis that increased PLC-delta 1 activity causes enhanced coronary vasomotility. Methods and Results-We generated transgenic (TG) mice with human R257H variant PLC-delta 1 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 F-2 alpha was similar among homozygous TG, heterozygous TG, and WT mice. Cultured rat aortic smooth muscle cells transfected with variant PLC-delta 1 showed a higher PLC activity than those with WT PLC-delta 1 (P<0.05) and furthermore showed greater intracellular Ca2+ response to acetylcholine in variant than in WT PLC-delta 1 (P<0.05). Conclusions-Increased PLC-delta 1 activity enhances coronary vasomotility such as that seen in patients with coronary spastic angina. (Circulation. 2012;125:1027-1036.)