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Antiarrhythmogenic Effect of Reconstituted High-Density Lipoprotein Against Ischemia/Reperfusion in Rats

Satoshi Imaizumi, MD^_*, Shin-ichiro Miura, MD, PhD^_*,_*, Kazuto Nakamura, MD, PhD^,, Yoshihiro Kiya, MD^_*, Yoshinari Uehara, MD, PhD^_*, Bo Zhang, PhD^_*, Yoshino Matsuo, PhD^_*, Hidenori Urata, MD, PhD, Munehito Ideishi, MD, PhD^_*, Kerry-Anne Rye, PhD^||, Masataka Sata, MD, PhD^, and Keijiro Saku, MD, PhD, FACC^_*

^_* Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan
Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Tokyo, Japan
Department of Advanced Clinical Science and Therapeutics, University of Tokyo Graduate School of Medicine, Tokyo, Japan
Department of Cardiovascular Diseases, Fukuoka University Chikushi Hospital, Chikushino, Japan
^|| Lipid Research Group, Heart Research Institute, Camperdown, Sydney, New South Wales, Australia.

Manuscript received September 14, 2007; revised manuscript received December 4, 2007, accepted December 10, 2007.

^_* Reprint requests and correspondence: Dr. Shin-ichiro Miura, Department of Cardiology, Fukuoka University School of Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan. (Email: miuras{at}cis.fukuoka-u.ac.jp).

Objectives: 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 (apolipoproteinA-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, apolipoproteinA-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. ApolipoproteinA-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.

Abbreviations and Acronyms   ABC = adenosine triphosphate-binding cassette transporter   A-I = apolipoproteinA-I   BP = blood pressure   cGMP = cyclic guanosine monophosphate   cITP = capillary isotachophoresis   EC = endothelial cell   ECG = electrocardiogram   eNOS = endothelial nitric oxide synthesis   ERK = extracellular-signal-regulated kinase   fHDL = fast-migrating high-density lipoprotein   HCECs = human coronary artery endothelial cell   HDL = high-density lipoprotein   HR = heart rate   I/R = ischemia/reperfusion   iHDL = intermediate-migrating high-density lipoprotein   L-NAME = N-nitro-L-arginine methyl ester hydrochloride   NO = nitric oxide   NOx = nitrite plus nitrate   PBS = phosphate-buffered saline   PI3 = phosphoinositide 3   POPC = 1-palmitoyl-2-oleoyl-phosphatidyl-choline   rHDL = reconstituted high-density lipoprotein   sHDL = slow-migrating high-density lipoprotein   SR-BI = scavenger receptor class B, type I

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