Enhanced p122RhoGAP/DLC-1 Expression Can Be a Cause of Coronary Spasm.
Enhanced p122RhoGAP/DLC-1 Expression Can Be a Cause of Coronary Spasm.
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DOI：
10.1371/journal.pone.0143884
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Okumura K
中科院分区：
文献类型：
--
作者：
Kinjo T;Tanaka M;Osanai T;Shibutani S;Narita I;Tanno T;Nishizaki K;Ichikawa H;Kimura Y;Ishida Y;Yokota T;Shimada M;Homma Y;Tomita H;Okumura K
我们先前的研究表明，在冠状动脉痉挛型心绞痛(CsA)患者中，磷脂酶C(PLC)-δ-1活性增加了3倍。我们还报道了作为PLC-δ1刺激物的p122Rho GTP酶激活蛋白/缺失的肝癌-1蛋白在CsA患者中表达上调。我们验证了p122RhoGAP/DLC-1过表达导致冠状动脉痉挛的假设。我们建立了血管平滑肌(VSM)特异性过表达p122RhoGAP/DLC-1的转基因(TG)小鼠。P122RhoGAP/DLC-1基因和蛋白在纯合子TG小鼠主动脉中的表达显著增加。抗p122RhoGAP/DLC-1抗体在TG组小鼠冠状动脉中的表达强于WT组小鼠。Tg纯合子培养的主动脉血管平滑肌细胞质膜部分和全细胞的PLC活性分别是WT小鼠的1.43倍和2.38倍。注射麦角新碱后，7只WT鼠中有1只(14%)、7只杂合子TG鼠中6只(84%)和7只纯合子TG鼠(100%)出现ST段抬高(P<；0.05，WT和TGS)。在分离的朗宁多夫心脏中，尽管TG和WT小鼠对前列腺素F2α的反应相似(n=5)，但TG和WT小鼠经麦角新碱治疗后冠脉灌流压升高，但在WT小鼠中无明显变化。仅在TG小鼠中记录到麦角新碱后冠状动脉局限性狭窄。VSM特异性过表达p122RhoGAP/DLC-1增强小鼠注射麦角新碱后的冠脉血管运动，这与人CsA有关。
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.