LOX-1 deletion decreases collagen accumulation in atherosclerotic plaque in low-density lipoprotein receptor knockout mice fed a high-cholesterol diet

• Published in: Cardiovascular research Vol. 79; no. 2; pp. 287 - 293
• Main Authors: Hu, Changping, Dandapat, Abhijit, Sun, Liuqin, Chen, Jiawei, Marwali, Muhammad R., Romeo, Francesco, Sawamura, Tatsuya, Mehta, Jawahar L.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 15.07.2008
• Subjects: Animals; Aorta - metabolism; Aorta - pathology; Atherosclerosis; Atherosclerosis (general aspects, experimental research); Atherosclerosis - metabolism; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cholesterol, Dietary - pharmacology; Collagen - metabolism; Extracellular matrix; Extracellular Matrix - metabolism; Fibronectins - metabolism; LOX-1; Male; Matrix metalloproteinases; Matrix Metalloproteinases - metabolism; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; NADPH oxidase; Nitric Oxide Synthase Type III - metabolism; Osteopontin - metabolism; Oxidative Stress - physiology; Proto-Oncogene Proteins c-akt - metabolism; Receptors, LDL - genetics; Receptors, LDL - metabolism; Scavenger Receptors, Class E - genetics; Scavenger Receptors, Class E - metabolism; Extracellular matrix; Matrix metalloproteinases; LOX-1; NADPH oxidase; Atherosclerosis; NADPH; Oxidase; Cardiovascular disease; Metalloendopeptidases; Phlebology; Accumulation; Vascular disease; Lipoprotein LDL; Atherosclerotic plaque; Deletion; Cardiology; Biological receptor; High; Enzyme; Rodentia; Cholesterol; Peptidases; Vertebrata; Mammalia; Decrease; Diet; Mouse; Animal; Collagen; Hydrolases; Oxidoreductases; Circulatory system
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1093/cvr/cvn110

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. 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 haem-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). Conclusion LOX-1 deletion reduces enhanced collagen deposition and MMP expression in atherosclerotic regions via inhibition of pro-oxidant signals.