Antiarrhythmogenic effect of reconstituted high-density lipoprotein against ischemia/reperfusion in rats.
OBJECTIVE
This study analyzed the antiarrhythmogenic effect of reconstituted high-density lipoprotein (rHDL) against ischemia/reperfusion in vivo.


BACKGROUND
Recent studies have suggested that a reduction in the plasma HDL level may contribute to cardiac sudden death. Although there are currently only a few therapeutic strategies for increasing HDL, an exciting new therapeutic option, rHDL, has recently been developed to prevent coronary artery disease.


METHODS
To analyze the suppression of reperfusion arrhythmia by rHDL (apolipoprotein A-I with 1-palmitoyl-2-oleoyl-phosphatidyl-choline), 92 male Wistar rats were divided into 10 groups: rats that had been pre-treated with or without rHDL, apolipoprotein A-I, or 1-palmitoyl-2-oleoyl-phosphatidyl-choline in the presence or absence of inhibitors of Akt protein kinase, nitric oxide (NO), or extracellular-signal-regulated kinase (ERK) administered intravenously before left coronary artery occlusion. We also used human coronary artery endothelial cells and adenosine triphosphate-binding cassette transporter (ABC) A1-, ABCG1-, or scavenger receptor class B, type I-transfected ldlA7 cells systems.


RESULTS
The duration of ventricular tachycardia or ventricular fibrillation after reperfusion in rHDL-pre-treated rats was much shorter than that in untreated rats. Apolipoprotein A-I or 1-palmitoyl-2-oleoyl-phosphatidyl-choline alone had no effect. The effect of rHDL was blocked by inhibitors of Akt, NO, and ERK. Plasma NO concentration in the rHDL group was significantly higher. In addition, rHDL activated phospho(p)-Akt, p-ERK, and p-endothelial NO synthesis in endothelial cells. The rHDL activated p-ERK in ABCA1- or ABCG1-transfected but not scavenger receptor class B, type I-transfected ldlA7 cells.


CONCLUSIONS
The rHDL-induced NO production, probably mediated by ABCA1 or ABCG1 through an Akt/ERK/NO pathway in endothelial cells, may suppress reperfusion-induced arrhythmias. The HDL-based therapy may hold the promise of reducing the incidence of such arrhythmias after ischemia/reperfusion.
Imaizumi
Satoshi
S
Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan.
Miura
Shin-ichiro
S
Nakamura
Kazuto
K
Kiya
Yoshihiro
Y
Uehara
Yoshinari
Y
Zhang
Bo
B
Matsuo
Yoshino
Y
Urata
Hidenori
H
Ideishi
Munehito
M
Rye
Kerry-Anne
KA
Sata
Masataka
M
Saku
Keijiro
K
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016632:Apolipoprotein A-I / Q000097:blood / Q000627:therapeutic use*; D008076:Cholesterol, HDL / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D004727:Endothelium; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000378:metabolism; D008297:Male; D017202:Myocardial Ischemia / Q000503:physiopathology* / Q000517:prevention & control; D015425:Myocardial Reperfusion / Q000009:adverse effects*; D009569:Nitric Oxide / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D017180:Tachycardia, Ventricular / Q000209:etiology / Q000503:physiopathology* / Q000517:prevention & control
D000889:Anti-Arrhythmia Agents; D016632:Apolipoprotein A-I; D008076:Cholesterol, HDL; D009569:Nitric Oxide; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases