Enhanced p122RhoGAP/DLC-1 Expression Can Be a Cause of Coronary Spasm

• Published in: PloS one Vol. 10; no. 12; p. e0143884
• Main Authors: Kinjo, Takahiko, Tanaka, Makoto, Osanai, Tomohiro, Shibutani, Shuji, Narita, Ikuyo, Tanno, Tomohiro, Nishizaki, Kimitaka, Ichikawa, Hiroaki, Kimura, Yoshihiro, Ishida, Yuji, Yokota, Takashi, Shimada, Michiko, Homma, Yoshimi, Tomita, Hirofumi, Okumura, Ken
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.12.2015; Public Library of Science (PLoS)
• Subjects: Angina; Angina pectoris; Angina Pectoris - metabolism; Animals; Aorta; Cardiology; Causes of; Cells, Cultured; Coronary artery; Coronary Vasospasm - metabolism; Coronary vessels; Coronary Vessels - metabolism; Experiments; Fibroblasts; Gene expression; Genetic aspects; GTPase-activating protein; GTPase-Activating Proteins - metabolism; GTPases; Guanosine triphosphatases; Hyperactivity; Hypertension; Injection; Kinases; Laboratory animals; Liver; Liver cancer; Medicine; Mice; Mice, Inbred C57BL; Mice, Transgenic; Muscle, Smooth, Vascular - metabolism; Muscles; Mutation; Nephrology; Patients; Perfusion; Phospholipase; Phospholipase C; Physiological aspects; Proteins; Rodents; Smooth muscle; Transgenic mice; Tumor Suppressor Proteins - metabolism; University graduates; Up-Regulation - physiology; Veins & arteries; Japan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0143884

We previously showed that phospholipase C (PLC)-δ1 activity was enhanced by 3-fold in patients with coronary spastic angina (CSA). We also reported that p122Rho GTPase-activating protein/deleted in liver cancer-1 (p122RhoGAP/DLC-1) protein, which was discovered as a PLC-δ1 stimulator, was upregulated in CSA patients. We tested the hypothesis that p122RhoGAP/DLC-1 overexpression causes coronary spasm. We generated transgenic (TG) mice with vascular smooth muscle (VSM)-specific overexpression of p122RhoGAP/DLC-1. The gene and protein expressions of p122RhoGAP/DLC-1 were markedly increased in the aorta of homozygous TG mice. Stronger staining with anti-p122RhoGAP/DLC-1 in the coronary artery was found in TG than in WT mice. PLC activities in the plasma membrane fraction and the whole cell were enhanced by 1.43 and 2.38 times, respectively, in cultured aortic vascular smooth muscle cells from homozygous TG compared with those from WT mice. Immediately after ergometrine injection, ST-segment elevation was observed in 1 of 7 WT (14%), 6 of 7 heterozygous TG (84%), and 7 of 7 homozygous TG mice (100%) (p<0.05, WT versus TGs). In the isolated Langendorff hearts, coronary perfusion pressure was increased after ergometrine in TG, but not in WT mice, despite of the similar response to prostaglandin F2α between TG and WT mice (n = 5). Focal narrowing of the coronary artery after ergometrine was documented only in TG mice. VSM-specific overexpression of p122RhoGAP/DLC-1 enhanced coronary vasomotility after ergometrine injection in mice, which is relevant to human CSA.