Abstract 16464: Coronary Vasospasm Induced in Transgenic Mouse With Vascular Smooth Muscle-Specific Overexpression of p122RhoGAP/DLC1
Background: We previously reported that the activity of phospholipase C (PLC)-δ1, a key enzyme for Ca2+ signaling in the coronary artery, was 3-fold enhanced in patients with coronary spastic angina (CSA), and it was positively correlated with coronary vasomotility (JACC 2000). We further showed that p122RhoGAP/DLC1 protein, which was recognized as a stimulator of PLCδ-1, was upregulated in CSA patients (ATVB 2010). In the present study, we tested the hypothesis that enhanced expression of p122RhoGAP/DLC1 causes coronary spasm, by using mice with vascular smooth muscle-specific overexpression of p122RhoGAP/DLC1.
Methods and Results: We generated transgenic mice overexpressing p122RhoGAP/ DLC1 protein under control of the mouse α-smooth muscle actin promoter (p122-Tg). The gene and protein expressions of p122RhoGAP/DLC1 were enhanced by 2-fold and 8-fold, respectively, in the aorta obtained from p122-Tg compared with wild type (WT) mice. Systolic blood pressure and pulse rate measured by tail-cuff method were both similar between p122-Tg and WT mice. No early mortality was found in p122-Tg mice until the age of 30 weeks. To induce coronary spasm, ergometrine (50 mg/kg) was injected into the jugular vein of the anesthetized mice, and the ECG in lead II was recorded continuously. At baseline, heart rate, PR interval, QRS duration, and QRS morphology were all similar between p122-Tg and WT mice. Immediately after ergometrine injection, remarkable ST segment elevation was observed in all p122-Tg (5/5), while it was not in WT mice (0/4, P<0.05 vs p122-Tg) (Figure). This ST segment elevation was followed by PR prolongation, AV dissociation and wide QRS, which are all suggestive of myocardial ischemia.
Conclusions: The present study demonstrated that upregulated p122RhoGAP/DLC1 was associated with enhanced coronary vasomotility after ergometrine injection. Upregulation of p122RhoGAP/DLC1 in the coronary artery can be a cause of coronary spasm in humans.
Author Disclosures: T. Kinjo: None. T. Osanai: None. M. Tanaka: None. K. Murakami: None. I. Narita: None. T. Tannno: None. K. Nishizaki: None. S. Shibutani: None. H. Tomita: None. K. Okumura: None.
- © 2014 by American Heart Association, Inc.