Please cite this article in press as: Borthwick F, et al. ApoA-1 infusion reduces arterial cholesterol and myocardial lesions in a rat model of cardiac dysfunction and insulin resistance. Atherosclerosis (2012), doi:10.1016/j.atherosclerosis.2012.03.006 ARTICLE IN PRESS G Model ATH-12497; No. of Pages 7 Atherosclerosis xxx (2012) xxx–xxx Contents lists available at SciVerse ScienceDirect Atherosclerosis jo ur nal homep age : www.elsevier.com/locate/atherosclerosis ApoA-1 infusion reduces arterial cholesterol and myocardial lesions in a rat model of cardiac dysfunction and insulin resistance Faye Borthwick a , Samantha Warnakula a , Rabban Mangat a , Richard R. Uwiera a , James C. Russell a , Sandra E. Kelly a,b , Candace Y. Lee c , Larry Hryshko c , John C.L. Mamo g , Kerry-Anne Rye d,e,f , Gary D. Lopaschuk b , Spencer D. Proctor a,∗ a Metabolic and Cardiovascular Diseases Laboratory, Molecular and Cell Biology of Lipids Group, Alberta Diabetes and Mazankowski Heart Institutes, Edmonton, Alberta, Canada b Cardiovascular Research Group, University of Alberta, Edmonton, Alberta, Canada c Institute for Cardiovascular Sciences, St Boniface Hospital, Winnipeg, Manitoba, Canada d Heart Research Institute, Sydney, Australia e Department of Medicine, University of Melbourne, Melbourne, Australia f School of Medicine, University of Western Sydney, Sydney, Australia g Division of Health Sciences, Curtin University of Technology & ATN Centre for Metabolic Health and Fitness, Perth, Australia a r t i c l e i n f o Article history: Received 24 June 2011 Received in revised form 5 March 2012 Accepted 6 March 2012 Available online xxx Keywords: Apolipoprotein-A1 High-density lipoprotein Insulin resistance Arterial cholesterol Cardiac dysfunction a b s t r a c t Objective: Low plasma high-density lipoprotein cholesterol (HDL-C) concentration is associated with the metabolic syndrome (MetS) and increased prevalence of cardiovascular disease (CVD). Animal and human studies report infusion of apolipoprotein A-1 (apoA-1) can reduce endothelial dysfunction, and/or induce regression of atherosclerosis. However, the direct mechanisms underlying the vascular benefits of either apoA-1 or HDL-C remain unclear. In this study, we assessed the ability of reconstituted HDL (rHDL) to improve vascular complications of MetS, including left ventricular (LV)-hypertrophy, arterial cholesterol deposition and myocardial lesion development. Methods and results: Obese insulin resistant (IR) JCR:LA-cp rats were infused with rHDL (0.4 mg/kg) over 3 days before assessing cardiac function (Echocardiography) at days 7 and 50 post-infusion, as well as haematoxylin and eosin staining of myocardial lesions at day 50. Acute ex vivo arterial cholesterol deposition was assessed with acute infusion of rHDL ex-vivo. Infusion of rHDL partially corrected abnormal diastolic compliance (18%; *p < 0.05) and improved parameters of cardiac function in IR rats. Further, acute rHDL infusion in carotid vessels reduced remnant lipoprotein associated-cholesterol deposition (30–86%; **p < 0.01) ex vivo in IR and male Wistar rats and reduced (41%; *p < 0.05) the frequency of early-stage myocardial lesions in IR rats. Conclusion: Short-term infusion of rHDL may beneficially reduce chronic vascular sequelae of MetS, including temporary improvement in LV-dysfunction, acute reduction of acute arterial cholesterol depo- sition and the development of early-stage myocardial lesions in the JCR:LA-cp rat. © 2012 Elsevier Ireland Ltd. All rights reserved. 1. Introduction Atherosclerosis that progresses to cardiovascular disease (CVD) is the main cause of death and disability in the Western world today (World Health Organization; 2009) [1]. Vascular disease contin- ues to affect millions each year, accounting for 17.1 million deaths worldwide in 2004, particularly those with obesity, the metabolic syndrome (MetS) and/or type II diabetes [2–4]. ∗ Corresponding author at: Alberta Diabetes Institute, 4-002J Li Ka Shing Centre for Health Research Innovation, University of Alberta, Edmonton, Alberta, T6G 2P5, Canada. Tel.: +1 780 492 4672; fax: +1 780 492 9270. E-mail addresses: J.Mamo@curtin.edu.au (J.C.L. Mamo), Spencer.Proctor@ualberta.ca, proctor@afhe.ualberta.ca (S.D. Proctor). Long-standing epidemiological evidence has demonstrated a significant and inverse correlation between low plasma high-density lipoprotein (HDL) and increased CVD risk [5,6]. Low concentrations of circulating HDL cholesterol have proven to be a more valuable and accurate predictor of CVD risk than high levels of the ‘classical’ atherogenic low-density lipoprotein (LDL) [7,8]. Indeed, subjects with low HDL cholesterol are often obese, insulin resistant (IR) and/or mildly hypertensive, indicative of early type II diabetes and the MetS [6]. Clinically, type II diabetics are at least five times greater at risk of developing CVD than those without diabetes and often have reduced and abnormal HDL (glycated and triglyceride enriched) [9–11], despite normal plasma concentra- tions of LDL. Collectively, these observations suggest the reduction in HDL levels during the early phase of diabetes may be of greater significance to CVD risk and the progression of atherosclerosis [2,3]. 0021-9150/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2012.03.006