Remnant lipoproteins from patients with sudden cardiac death enhance coronary vasospastic activity through upregulation of Rho-kinase.
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.


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.
Oi
Keiji
K
Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
Shimokawa
Hiroaki
H
Hiroki
Junko
J
Uwatoku
Toyokazu
T
Abe
Kohtaro
K
Matsumoto
Yasuharu
Y
Nakajima
Yasuhiro
Y
Nakajima
Katsuyuki
K
Takeichi
Sanae
S
Takeshita
Akira
A
D000328:Adult; D000368:Aged; D000818:Animals; D002478:Cells, Cultured / Q000187:drug effects; D003329:Coronary Vasospasm / Q000139:chemically induced*; D016757:Death, Sudden, Cardiac; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008074:Lipoproteins / Q000097:blood / Q000302:isolation & purification / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics; D012701:Serotonin / Q000494:pharmacology; D016037:Single-Blind Method; D013552:Swine; D014661:Vasoconstriction / Q000187:drug effects; D054460:rho-Associated Kinases
D047908:Intracellular Signaling Peptides and Proteins; D008074:Lipoproteins; D012701:Serotonin; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases