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    Journal of the American College of Cardiology Vol. 51, No. 16, 2008 2008 by the American College of Cardiology Foundation ISSN 0735-1097/08/$34.00P

    Antiarrhythmogenic Effect of Reconstituted High-DensityLipoprotein 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, Keijiro Saku, MD, PHD, FACC*

    Fukuoka, Tokyo, and Chikushino, Japan; and Sydney, Australia

    Objectives This study analyzed the antiarrhythmogenic effect of reconstituted high-density lipoprotein (rHDL) againstischemia/reperfusion in vivo.

    Background Recent studies have suggested that a reduction in the plasma HDL level may contribute to cardiac suddendeath. Although there are currently only a few therapeutic strategies for increasing HDL, an exciting new thera-peutic 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 orwithout rHDL, apolipoproteinA-I, or 1-palmitoyl-2-oleoyl-phosphatidyl-choline in the presence or absence of inhibi-tors of Akt protein kinase, nitric oxide (NO), or extracellular-signal-regulated kinase (ERK) administered intrave-nously before left coronary artery occlusion. We also used human coronary artery endothelial cells and adeno-sine triphosphate-binding cassette transporter (ABC) A1-, ABCG1-, or scavenger receptor class B, typeItransfected ldlA7 cells systems.

    Results The duration of ventricular tachycardia or ventricular fibrillation after reperfusion in rHDLpre-treated rats wasmuch shorter than that in untreated rats. ApolipoproteinA-I or 1-palmitoyl-2-oleoyl-phosphatidyl-choline alonehad no effect. The effect of rHDL was blocked by inhibitors of Akt, NO, and ERK. Plasma NO concentration in therHDL group was significantly higher. In addition, rHDL activated phospho(p)-Akt, p-ERK, and p-endothelial NOsynthesis in endothelial cells. The rHDL activated p-ERK in ABCA1- or ABCG1-transfected but not scavenger re-ceptor class B, type Itransfected ldlA7 cells.

    Conclusions The rHDL-induced NO production, probably mediated by ABCA1 or ABCG1 through an Akt/ERK/NO pathway inendothelial cells, may suppress reperfusion-induced arrhythmias. The HDL-based therapy may hold the promiseof reducing the incidence of such arrhythmias after ischemia/reperfusion. (J Am Coll Cardiol 2008;51:160412) 2008 by the American College of Cardiology Foundation

    ublished by Elsevier Inc. doi:10.1016/j.jacc.2007.12.040

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    lasma high-density lipoprotein (HDL) protects againstardiac events by mediating cholesterol efflux from therterial wall (reverse cholesterol transport), thereby prevent-ng the formation of atherosclerotic plaque in coronaryrteries (1). Recent studies have suggested that a reduction

    rom the *Department of Cardiology, Fukuoka University School of Medicine,ukuoka, Japan; Department of Cardiovascular Medicine, and the Department ofdvanced Clinical Science and Therapeutics, University of Tokyo Graduate School ofedicine, Tokyo, Japan; Department of Cardiovascular Diseases, Fukuoka Univer-

    ity Chikushi Hospital, Chikushino, Japan; and the Lipid Research Group, Heartesearch Institute, Camperdown, Sydney, New South Wales, Australia. Supported inart by a grant (18590826) from the Ministry of Education, Culture, Sports, Sciencend Technology, Japan, and the Central Research Institute of Fukuoka University,apan.

    HManuscript received September 14, 2007; revised manuscript received December 4,

    007, accepted December 10, 2007.

    n the plasma HDL level may contribute to cardiac suddeneath (2). This contribution of HDL must be related toeverse cholesterol transport and the stabilization of vulner-ble, unstable plaque (3). There are several reports thatuggest a direct relation between plasma high- and low-ensity lipoproteins and fatal arrhythmia (4,5). Further-ore, HDL has many pleiotropic effects (1), such as

    ntioxidant, anti-inflammatory, and antithrombotic proper-ies, in addition to its ability to enhance reverse cholesterolransport. Although HDL is a target in the treatment oftherosclerotic coronary artery disease, there are currentlynly a few therapeutic strategies for increasing HDL, suchs statins and cholesterol ester transfer protein inhibitors.owever, an exciting new therapeutic option, reconstituted

    DL (rHDL), has recently been developed and is currently

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    1605JACC Vol. 51, No. 16, 2008 Imaizumi et al.April 22, 2008:160412 Antiarrhythmogenic Effect of HDL

    he focus of intriguing research (6). Although pleiotropicffects of rHDL may protect isolated rat hearts against anschemia/reperfusion (I/R) injury that involves the reductionf tumor necrotic factor- and the enhancement of prosta-landin release (7), the antiarrhythmogenic effect of rHDLgainst I/R remains unclear in vivo.

    Nitric oxide (NO) is an endogenous regulatory moleculehat is involved in a variety of physiological activities such ashe regulation of blood pressure (BP). A previous in vitrotudy examined HDL-stimulated NO release (1). In addi-ion, NO is also known to trigger ischemic preconditioninggainst I/R arrhythmia (8). For instance, an angiotensineceptor blocker induced an antiarrhythmogenic effect (9)hat may be related to NO production in animal I/R models10). Because NO is a key mediator for antiarrhythmogenicffects, HDL-induced NO production may protect theeart from cardiac injury during I/R via effects on bothardiac tissue and coronary perfusion. Therefore, we hypoth-sized that rHDL contributed to the prevention of I/Rrrhythmia through its pleiotropic effects, such as NO pro-uction in endothelial cells (ECs). In this study, we ana-

    yzed the antiarrhythmogenic effect of rHDL using a rat I/Rrrhythmia model and cell systems.

    ethods

    aterials. The following antibodies and reagents wereurchased or kindly provided: PD98059, a specific inhib-tor of extracellular-signal-regulated kinase (ERK) (Cellignaling Technology Inc, Danvers, Massachusetts);-nitro-L-arginine methyl ester hydrochloride (L-AME), a specific inhibitor of endothelial NO synthase

    eNOS) (Sigma-Aldrich Co., St. Louis, Missouri); wort-annin, a specific inhibitor of phosphoinositide 3 (PI3)

    inase (Sigma-Aldrich); antibodies for Akt, phospho(p)-kt, ERK1/2, and p-ERK1/2 (Thr202/Tyr204) (Cell Sig-aling Technology).reparation of rHDL. Discoidal rHDL containing 1-almitoyl-2-oleoyl-phosphatidyl- choline (POPC) (Avantiolar Lipids, Alabaster, Alabama) and apolipoproteinA-I

    A-I) (initial POPC/A-I molar ratio 100/1) was preparedy the cholate dialysis method as described previously (11).nimal preparation. Male Wistar rats (250 to 350 g) were

    nesthetized with 1.5% pentobarbital (60 mg/kg) intraperi-oneally. Subdermal electrodes were placed to allow theetermination of a lead II electrocardiogram (ECG). Myo-ardial ischemia was induced by temporary occlusion of theeft main coronary artery. After tracheotomy, the animalsere ventilated with room air by a respirator for small

    odents (model 683; Harvard rodent ventilator, Harvardpparatus, Inc., Holliston, Massachusetts). The chest waspened by a left thoracotomy and the heart was exposed.fter incision of the pericardium to allow access to the leftain coronary artery, the hearts were subjected to 5 min of

    schemia by ligation the left main coronary artery with #6/0

    ilk string. The string was removed after 5 min of coronary 1

    cclusion to produce reperfusion.fter 3 min of reperfusion, blood

    amples were drawn by cardiacuncture and the heart was rap-dly excised. Before and duringhe ischemia or reperfusion pe-iod, ECGs were recorded on aowerLab 4/25 data acquisitionystem (ADInstruments, Colo-ado Springs, Colorado) with datanalysis software (Chart v4.0, AD-nstruments). Ventricular arrhyth-ia was assessed in accordanceith the definitions reported in theambeth Convention (12), and

    he incidence and duration of ven-ricular tachycardia (defined as 4 orore consecutive ventricular pre-ature beats) and ventricular fi-

    rillation (if an irregular undulat-ng baseline was apparent) wereetermined. All studies were per-ormed in accordance with theuidelines described in the na-ional animal protection law, andhe use of animal tissues was ap-roved by the Fukuoka Universitynternal Review Committee.xperimental protocols. EXPER-

    MENT 1. The effects of rHDL onCG properties, BP, heart rate

    HR), and cardiac function weretudied. The rHDL (6 mg/kg of-I) was injected intravenously

    nto rats under sedation (pento-arbital, intraperitoneally). Inhe control group, phosphate-uffered saline (PBS) was infusednstead of rHDL. Changes inCG properties (PR, QRS, andT intervals), BP, and HR were

    ecorded before injection and 10nd 15 min after injection. TheP and HR were measured withBP monitor (MK1100, Muro-achi Kikai Co., Tokyo, Japan). Cardiac function was also

    ecorded at the same time by transthoracic echocardiogra-hy (NEMIO SSA-550A, Toshiba, Tokyo, Japan). Short-nd long-axis 2-dimensional views and M-mode at the levelf papillary muscle were analyzed, and the ejection fractionas calculated as [100 (volume in diastole-volume in

    ystole)/volume in diastole].

    XPERIMENT 2. The experimental design is shown in Figure. Ninety-two male Wistar rats were randomly assigned to

    Abbreviationsand Acronym