Oi Keiji, Shimokawa Hiroaki, Hiroki Junko, Uwatoku Toyokazu, Abe Kohtaro, Matsumoto Yasuharu, Nakajima Yasuhiro, Nakajima Katsuyuki, Takeichi Sanae, Takeshita Akira
Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
Arterioscler Thromb Vasc Biol. 2004 May;24(5):918-22. doi: 10.1161/01.ATV.0000126678.93747.80. Epub 2004 Mar 25.
Sudden cardiac death (SCD) still remains a serious problem. We have previously shown that remnant-like particles (RLP) are the major risk factor for SCD and that Rho-kinase plays a central role in the molecular mechanism of coronary vasospasm. In this study, we examined whether RLP from patients with SCD upregulate Rho-kinase associated with an enhanced coronary vasospastic activity.
We isolated RLP and non-RLP in very-low-density lipoprotein (VLDL) fraction from SCD patients without coronary stenosis. We performed in vivo study in which we treated the coronary artery with RLP or non-RLP fraction at the adventitia in pigs. After 1 week, intracoronary serotonin caused marked coronary hyperconstriction at the segment treated with RLP fraction but not with non-RLP fraction (P<0.001, n=6), and hydroxyfasudil, a selective Rho-kinase inhibitor, dose-dependently inhibited the spasm in vivo. In organ chamber experiments, serotonin caused hypercontraction of vascular smooth muscle cells (VSMC) from RLP-treated segment, which was significantly inhibited by hydroxyfasudil (P<0.001, n=6). In cultured human coronary VSMC, the treatment with RLP significantly enhanced the expression and activity of Rho-kinase (P<0.05, n=6).
These results indicate that RLP from SCD patients upregulate Rho-kinase in coronary VSMC and markedly enhance coronary vasospastic activity.
心源性猝死（SCD）仍然是一个严重的问题。我们之前已经表明，残留样颗粒（RLP）是SCD的主要危险因素，并且Rho激酶在冠状动脉痉挛的分子机制中起核心作用。在本研究中，我们检测了SCD患者的RLP是否上调与冠状动脉痉挛活性增强相关的Rho激酶。
我们从无冠状动脉狭窄的SCD患者的极低密度脂蛋白（VLDL）组分中分离出RLP和非RLP。我们进行了一项体内研究，在猪的冠状动脉外膜处用RLP或非RLP组分进行处理。1周后，冠状动脉内注射5-羟色胺在RLP组分处理的节段引起明显的冠状动脉过度收缩，而非RLP组分处理的节段则未出现（P<0.001，n=6），并且选择性Rho激酶抑制剂羟基法舒地尔在体内剂量依赖性地抑制痉挛。在器官浴槽实验中，5-羟色胺引起RLP处理节段的血管平滑肌细胞（VSMC）过度收缩，羟基法舒地尔可显著抑制（P<0.001，n=6）。在培养的人冠状动脉VSMC中，用RLP处理显著增强了Rho激酶的表达和活性（P<0.05，n=6）。
这些结果表明，SCD患者的RLP上调冠状动脉VSMC中的Rho激酶，并显著增强冠状动脉痉挛活性。
