title: LOX-1 inhibition in myocardial ischemia-reperfusion injury: modulation of MMP-1 and inflammation.
abstract: A recently identified lectin-like oxidized low-density lipoprotein receptor (LOX-1) mediates endothelial cell injury and facilitates inflammatory cell adhesion. We studied the role of LOX-1 in myocardial ischemia-reperfusion (I/R) injury. Anesthetized Sprague-Dawley rats were subjected to 60 min of left coronary artery (LCA) ligation, followed by 60 min of reperfusion. Rats were treated with saline, LOX-1 blocking antibody JXT21 (10 mg/kg), or nonspecific anti-goat IgG (10 mg/kg) before I/R. Ten other rats underwent surgery without LCA ligation and served as a sham control group. LOX-1 expression was markedly increased during I/R (P < 0.01 vs. sham control group). Simultaneously, the expression of matrix metalloproteinase-1 (MMP-1) and adhesion molecules (P-selectin, VCAM-1, and ICAM-1) was also increased in the I/R area (P < 0.01 vs. sham control group). There was intense leukocyte accumulation in the I/R area in the saline-treated group. Treatment of rats with the LOX-1 antibody prevented I/R-induced upregulation of LOX-1 and reduced MMP-1 and adhesion molecule expression as well as leukocyte recruitment. LOX-1 antibody, but not nonspecific IgG, also reduced myocardial infarct size (P < 0.01 vs. saline-treated I/R group). To explore the link between LOX-1 and adhesion molecule expression, we measured expression of oxidative stress-sensitive p38 mitogen-activated protein kinase (p38 MAPK). The activity of p38 MAPK was increased during I/R (P < 0.01 vs. sham control), and use of LOX-1 antibody inhibited p38 MAPK activation (P < 0.01). These findings indicate that myocardial I/R upregulates LOX-1 expression, which through p38 MAPK activation increases the expression of MMP-1 and adhesion molecules. Inhibition of LOX-1 exerts an important protective effect against myocardial I/R injury.
authors.affiliation: Department of Internal Medicine, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, 4301 West Markham, Little Rock, AR 72205, USA.
authors.forename: Dayuan
authors.initials: D
authors.lastname: Li
authors.forename: Victor
authors.initials: V
authors.lastname: Williams
authors.forename: Ling
authors.initials: L
authors.lastname: Liu
authors.forename: Hongjiang
authors.initials: H
authors.lastname: Chen
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Sawamura
authors.forename: Tamim
authors.initials: T
authors.lastname: Antakli
authors.forename: Jawahar L
authors.initials: JL
authors.lastname: Mehta
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D015815:Cell Adhesion Molecules / Q000235:genetics; D015870:Gene Expression; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009203:Myocardial Infarction / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D018375:Neutrophil Activation / Q000276:immunology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011973:Receptors, LDL / Q000235:genetics / Q000276:immunology*; D051131:Receptors, Oxidized LDL; D051127:Scavenger Receptors, Class E; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D000906:Antibodies; D015815:Cell Adhesion Molecules; C495136:OLR1 protein, rat; D011973:Receptors, LDL; D051131:Receptors, Oxidized LDL; D051127:Scavenger Receptors, Class E; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020781:Matrix Metalloproteinase 1