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

PLoS One. 2015 Dec 1;10(12):e0143884. doi: 10.1371/journal.pone.0143884. eCollection 2015.


Background: 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.

Methods and results: 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.

Conclusions: VSM-specific overexpression of p122RhoGAP/DLC-1 enhanced coronary vasomotility after ergometrine injection in mice, which is relevant to human CSA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angina Pectoris / metabolism
  • Animals
  • Cells, Cultured
  • Coronary Vasospasm / metabolism*
  • Coronary Vessels / metabolism*
  • GTPase-Activating Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Muscle, Smooth, Vascular / metabolism*
  • Tumor Suppressor Proteins / metabolism*
  • Up-Regulation / physiology


  • DLC-1 (deleted in liver cancer) protein, mouse
  • GTPase-Activating Proteins
  • Tumor Suppressor Proteins

Grant support

This study was supported in part by grant-in-aid for scientific research 26461120 from Japan Society for the Promotion of Science of Japan (http://www.jsps.go.jp/english/) to Dr. Okumura, and 25860577 to Dr. Yokota, the Takeda Science Foundation (http://www.takeda-sci.or.jp/) to Dr. Tomita, Japan Heart Foundation and Astellas/Pfizer Grant for Research on Atherosclerosis Update (http://www.jhf.or.jp/josei/12_update/) to Dr. Shibutani. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.