Coronary Vasospasm Induced in Transgenic Mouse with the Increased Phospholipase C-δ1 Activity
Background—We reported that phospholipase C (PLC)-δ1 activity was enhanced by 3 times in patients with coronary spastic angina (CSA). 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.
Methods and 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 (HomoTG) and heterozygous TG (HeteroTG) compared with wild type mice (WT). ST elevation after ergometrine occurred in 17 of 18 HomoTG, 6 of 20 HeteroTG and 3 of 22 WT (p<0.01, HomoTG versus WT; p<0.05, HomoTG versus HeteroTG; p=NS, HeteroTG versus WT). ST elevation was associated with bradyarrhythmias in HomoTG. Focal coronary artery narrowing was documented with microvascular filling technique in 3 of 5 HomoTG after ergometrine but not in any of 7 WT (p<0.05). In the isolated Langendorff hearts, coronary perfusion pressure (CPP) was increased after ergometrine in HomoTG (p<0.01), but not in HeteroTG or WT. CPP increase after prostaglandin F2α was similar among HomoTG, HeteroTG, and WT. Cultured rat aortic smooth muscle cells transfected with variant PLC-δ1 showed a higher PLC activity than those with wild PLC-δ1 (p<0.05), and further showed greater intracellular Ca2+ response to acetylcholine in variant than in wild PLC-δ1 (p<0.05).
Conclusions—Increased PLC-δ1 activity enhances coronary vasomotility such as seen in patients with CSA.
- Received August 27, 2011.
- Accepted January 13, 2012.
- Copyright © 2012, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited