Abstract 13236: Coronary Vasospasm Induced in Transgenic Mouse With Overexpression of p122RhoGAP/DLC1
Backgrounds: We reported that the activity of phospholipase C (PLC)-δ1, a key enzyme for Ca2+ signaling in the artery, was 3-fold enhanced in patients with coronary spastic angina (CSA), and was positively correlated with coronary vasomotility. We recently showed that p122RhoGAP/DLC1 (DLC1) protein, which was discovered as a stimulator of PLCδ-1, was upregulated in CSA patients. We tested the hypothesis that overexpression of DLC1 cause coronary spasm in mice.
Methods and Results: We generated transgenic (TG) C57BL/6J mice with vascular smooth muscle-specific overexpression of DLC1. The gene and protein expression of DLC1 was enhanced by 11-fold and 4.4-fold, respectively, in the homozygous TG aorta compared with wild type (WT) mice. Systolic blood pressure and heart rate measured by tail-cuff method were similar between TG and WT mice, and no early mortality was found until the age of 30 weeks. PLC enzymatic activities in the plasma membrane and the whole cell were enhanced by 1.4 and 2.0 times, respectively, in cultured aortic vascular smooth muscle cells from homozygous TG compared with those from WT. To induce coronary spasm, ergometrine at 50 mg/kg was injected into the jugular vein of the anesthetized mice, and the ECG in lead II was recorded continuously. Heart rate, PR interval, QRS duration, and QRS morphology at baseline were all similar between TG and WT mice. Immediately after ergometrine injection, ST segment elevation was observed in one of 7 WT (14%), 6 of 7 heterozygous TG (84%), and 7 of 7 homozygous TG mice (100%) (both p<0.05, WT vs TGs). This ST segment elevation in TG was followed by atrioventricular conduction disturbance and wide QRS rhythm, which are suggestive of myocardial ischemia. In the isolated Langendorff hearts, coronary perfusion pressure was increased after ergometrine in homozygous TG mice but not in WT mice despite the fact that the response to prostaglandin F2α was similar between TG and WT mice (n=5). In the group treated with ergometrine, focal narrowing of the coronary artery was documented only in TG mice (2 lesions in 2 hearts).
Conclusion: Upregulated DLC1 caused enhanced coronary vasomotility after ergometrine injection in mice. Upregulation of DLC1 in the coronary artery can be a cause of coronary spasm in humans.
Author Disclosures: T. Kinjo: None. M. Tanaka: None. T. Osanai: None. I. Narita: None. T. Tannno: None. K. Nishizaki: None. S. Shibutani: None. Y. Ishida: None. H. Tomita: None. Y. Homma: None. K. Okumura: None.
- © 2015 by American Heart Association, Inc.