Cardiovascular Research Advance Access [Accepted Manuscript] published online on May 3, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn110
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LOX-1 deletion decreases collagen accumulation in atherosclerotic plaque in LDL receptor knockout mice fed a high cholesterol diet
a Department of Internal Medicine, Central Arkansas Veterans Healthcare System and the University of Arkansas for Medical Sciences, Little Rock, AR, USA
b Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, China
c Department of Ophthalmology, Heping Hospital, Changzhi Medical College, Changzhi, China
d Department of Cardiology, University of Rome "Tor Vergata", Rome, Italy
e Department of Vascular Physiology, National Cardiovascular Center Research Institute, Suita, Osaka, Japan
* Corresponding author: J.L. Mehta, MD, PhD University of Arkansas for Medical Sciences 4301 West Markham St. Slot 532, Little Rock, AR 72205 Tel. 501-686-5046 Fax 501-686-6180 Email: mehtaJL{at}uams.edu
Aims: Collagen, as a component of the extracellular matrix, has been linked to atherosclerotic plaque formation and stability. Activation of LOX-1, a lectin-like oxidized low density lipoproteins (LDL) receptor-1, exerts a significant role in collagen formation. We examine the hypothesis that LOX-1 deletion may inhibit collagen accumulation in atherosclerotic arteries in LDL receptor (LDLR) knockout (KO) mice.
Methods and results: We generated LOX-1 KO and LOX-1/LDLR double KO mice on a C57BL/6 (wild-type mice) background, and fed a 4% cholesterol/10% cocoa butter diet for 18 weeks. Vessel wall collagen accumulation was increased in association with atherogenesis in the LDLR KO mice (P<0.01 vs. wild-type mice), but much less so in the double KO mice (P<0.01 vs. LDLR KO mice). Collagen accumulation data were corroborated with pro-collagen I measurements. Expression/activity of osteopontin, fibronectin and matrix metalloproteinases (MMP-2 and MMP-9) was also increased in the LDLR KO mice (P<0.01 vs. wild-type mice), but not in the mice with LOX-1 deletion (P<0.01 vs. LDLR KO mice). The expression of NADPH oxidase (p47phox, p22phox, gp91phox and Nox-4 subunits) and nitrotyrosine was increased in the LDLR KO mice (P<0.01 vs. wild-type mice) and not in mice with LOX-1 deletion (P<0.01 vs. LDLR KO mice). Phosphorylation of Akt-1 and endothelial nitric oxide synthase and expression of heme oxygenase-1 were found to be reduced in the LDLR KO mice (P<0.01 vs. wild-type mice), but not in the mice with LOX-1 deletion (P<0.01 vs. LDLR KO mice).
Conclusions: LOX-1 deletion reduces enhanced collagen deposition and MMP expression in atherosclerotic regions via inhibition of pro-oxidant signals.
KEYWORDS Atherosclerosis; LOX-1; Extracellular matrix; Matrix metalloproteinases; NADPH oxidase
Time for primary review: 21 days
1 These two authors (CH and AD) contributed equally to this work.
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