on March 25, 2004
Published online before print March 25, 2004, doi: 10.1161/01.ATV.0000126678.93747.80
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Submitted on January 10, 2004
Accepted on March 15, 2004
Remnant Lipoproteins From Patients with Sudden Cardiac Death Enhance Coronary Vasospastic Activity Through Upregulation of Rho-kinase
Keiji Oi ;
From the Department of Cardiovascular Medicine (K.O, H.S., J.H., T.U., K.A., Y.M., A.T.), Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan; Kyushu University COE Program on Lifestyle-Related Diseases (H.S.), Fukuoka, Japan; Department of Forensic Medicine (Y.N., S.T.), Tokai University School of Medicine, Isehara, Japan; and Immunoresearch Laboratories Co (K.N.), Takasaki, Japan.
* To whom correspondence should be addressed. E-mail: shimo{at}cardiol.med.kyushu-u.ac.jp.
Objective--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.
Methods and Results--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).
Conclusions--These results indicate that RLP from SCD patients upregulate Rho-kinase in coronary VSMC and markedly enhance coronary vasospastic activity.
Key words: sudden cardiac death • lipoproteins • coronary vasospasm
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