Abstract 12834: Coronary Vasospasm Induced In Transgenic Mice With Variant Phospholipase C-δ1 (R257H)
Background: We previously showed that the activity of phospholipase C (PLC)-δ1, a key enzyme for Ca2+ signaling in the coronary artery, was enhanced by 3 times in patients with coronary spastic angina (CSA), and was positively correlated with coronary vasomotility. We further showed that PLC-δ1 structural mutation, 864G-A variant, with the amino acid replacement of arginine 257 by histidine (R257H) was detected in CSA patients, and this variant PLC-δ1 activity was enhanced by 2 times. We examined the direct and causative role of structural mutant PLC-δ1 in the genesis of coronary spasm by generating the R257H variant PLC-δ1 overexpressing transgenic mice (TG).
Methods and Results: In TG, the introduced human R257H variant PLC-δ1 gene was upregulated by 2 times in aorta. Double-staining with immunofluorescence microscopy comfirmed the enhanced PLC-δ1 expression in the coronary artery smooth muscle cells. TG showed elevated systolic arterial pressure by 6 mmHg (p<0.05) compared with wild type littermate mice (WT) but no early mortality. Heart rate and body weight were similar between TG and WT. Ergometrine at 15 and 50 mg/kg was injected into the carotid vein additively, and ECG was monitored continuously. ST segment elevation was more frequently observed in TG compare with WT after ergometrine at 15 mg/kg (6/17 in TG vs 1/22 in WT, P<0.05) and 50 mg/kg (18/18 in TG vs 3/22 in WT, P<0.01). Concomitantly with ST segment elevation, atrioventricular block or sinus bradycardia was observed. To further examine the morphological changes in the coronary artery, the microvascular filling technique was used. Microvascular coronary spasm after injection of ergometrine was documented in TG but not in WT. Coronary perfusion pressure (mmHg) was measured in the isolated Langendorff heart. In WT, it did not change after administration of ergometrine (69±12 vs 85±16, n=8, p=ns), while in TG, it remarkably increased (65±10 vs 106±42, n=11, p<0.01).
Conclusions: In the R257H variant PLC-δ1 expressing transgenic mice, the coronary vasoconstrictor response to ergometrine was enhanced, which resulted in myocardial ischemia. Thus, the R257H variant PLC-δ1 gene disclosed in the CSA patients is one of the causes of coronary spasm.
- © 2010 by American Heart Association, Inc.