EXPERIMENTAL STUDY
Expression of lectin-like oxidized low-density lipoprotein receptors during ischemia-reperfusion and its role in determination of apoptosis and left ventricular dysfunction
Dayuan Li, MD, PhD*,
Victor Williams, MD*,
Ling Liu, MD*,
Hongjiang Chen, MD*,
Tatsuya Sawamura, MD, PhD ,
Francesco Romeo, MD, FACC and
Jawahar L. Mehta, MD, PhD, FACC*,*
* Departments of Internal Medicine, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, USA
Department of Bioscience, National Cardiovascular Center Research Institute, Osaka, Japan
Department of Cardiology, University of Rome "Tor Vergata," Rome, Italy
Manuscript received February 26, 2002;
revised manuscript received September 30, 2002,
accepted November 27, 2002.
* Reprint requests and correspondence: Dr. Jawahar L. Mehta, University of Arkansas for Medical Sciences, 4301 West Markham, Slot 532, Little Rock, Arkansas 72205, USA.
mehtajl{at}uams.edu
OBJECTIVES: The goal of this study was to determine the role of lectin-like oxidized low-density lipoprotein receptors (LOX-1), a recently identified oxidized low-density lipoprotein (ox-LDL) receptor, in ischemia-reperfusion injury to the heart.
BACKGROUND: Reactive oxygen species (ROS) released during ischemia-reperfusion oxidize low-density lipoproteins; LOX-1 is upregulated by ox-LDL and ROS, and is involved in cell injury.
METHODS: Anesthetized rats were subjected to left coronary artery ligation for 60 min (n = 10, ischemia group), or ischemia followed by 60 min of reperfusion (n = 30, ischemia-reperfusion group). Rats in the latter group were treated with saline, the LOX-1 blocking antibody JXT21 (10 mg/kg), or nonspecific anti-goat immunoglobulin G (IgG) (10 mg/kg). Ten other rats underwent thoracotomy without coronary ligation (sham control).
RESULTS: Ischemia-reperfusion was associated with an increase in LOX-1 expression, lipid peroxidation and apoptosis, a large infarct area, and a decrease in left ventricular function (all, p < 0.01 vs. sham control and ischemia alone groups). Treatment of rats with LOX-1 antibody prevented ischemia-reperfusion–induced upregulation of LOX-1. Importantly, the LOX-1 antibody reduced apoptosis by 48%, lipid peroxidation by 39%, and myocardial infarct size by 45%, and improved left ventricular function (first derivative of pressure measured over time: –47% to –18%, p < 0.01). Nonspecific IgG had no effect.
CONCLUSIONS: Lectin-like oxidized low-density lipoprotein receptors are upregulated during myocardial ischemia-reperfusion, and appear to be associated with apoptosis, necrosis, and left ventricular functional deterioration.
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Abbreviations and Acronyms
| | IgG | | immunoglobulin G | | LOX-1 | | lectin-like oxidized low-density lipoprotein receptors | | mRNA | | messenger ribonucleic acid | | ox-LDL | | oxidized low-density lipoprotein | | ROS | | reactive oxygen species | | TTC | | triphenyl tetrazolium chloride | | TUNEL | | terminal dUTP nick end-labeling |
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