期刊
CARDIOVASCULAR RESEARCH
卷 79, 期 2, 页码 287-293出版社
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvn110
关键词
atherosclerosis; LOX-1; extracellular matrix; matrix metalloproteinases; NADPH oxidase
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 lipoprotein (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. wildtype 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 ( p47(phox), p22(phox), gp91(phox), 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 haem-oxygenase-1 were found to be reduced in the LDLR KO mice ( P < 0.01 vs. wildtype mice), but not in the mice with LOX-1 deletion ( P < 0.01 vs. LDLR KO mice). Conclusion LOX-1 deletion reduces enhanced collagen deposition and MMP expression in atherosclerotic regions via inhibition of pro-oxidant signals.
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