Monocyte chemotactic protein-1 gene and protein expression in atherogenesis of hypercholesterolemic rabbits.
Monocyte adherence to the endothelium and subsequent migration into the subendothelial space are important early events in atherogenesis. Monocyte chemotactic protein-1 (MCP-1) has been shown to be highly expressed in both human atheroma and advanced atherosclerotic lesions of experimental animals. To establish the temporal correlation between MCP-1 expression and plaque development, we examined the expression of MCP-1 during atherogenesis of hypercholesterolemic rabbits using Northern blot analysis, in situ hybridization, and immunohistochemistry. New Zealand White rabbits were fed with 2% cholesterol-containing diet for 1 day, 3 days, 1 week, 3 weeks or 6 weeks. The plasma levels of total cholesterol were significantly increased 3 days after cholesterol feeding and continued to increase during the entire cholesterol-feeding period. Northern blot analysis showed that MCP-1 mRNA levels remained unchanged following cholesterol feeding for up to 1 week, were higher than control levels at 3-week and increased even higher at 6-week. In situ hybridization showed that after 3 weeks of cholesterol feeding, MCP-1 mRNA expression was up-regulated in newly-formed fatty streaks and parts of tunica media in the presence or absence of fatty streaks. At 6-week, pronounced MCP-1 mRNA expression was detected with similar distribution. In contrast, MCP-1 mRNA was detected only in a few endothelial cells and adventitia in control and experimental groups feeding cholesterol up to 1-week. Immunostaining of serial sections indicated that MCP-1 was expressed by macrophages and smooth muscle cells in rabbits fed with cholesterol for 3 or 6 weeks. No MCP-1 was detected in intima or media in all other groups. These results show that a lag period exists between serum cholesterol increase and upregulation of MCP-1 expression, suggesting that cholesterol modifications (e.g. oxidation) are required to stimulate MCP-1 expression. In addition, MCP-1 expressed by both macrophages and smooth muscle cells during the initial stages of atherosclerosis is likely to contribute to the development of fatty streaks in hypercholesterolemic rabbits.
Chen
Y L
YL
Institute of Anatomy, National Yang-Ming University, Shih-Pai, Taipei, Taiwan, ROC.
Chang
Y J
YJ
Jiang
M J
MJ
D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001161:Arteriosclerosis / Q000209:etiology / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D015152:Blotting, Northern; D018932:Chemokine CCL2 / Q000235:genetics*; D002784:Cholesterol / Q000097:blood; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D015870:Gene Expression; D006937:Hypercholesterolemia / Q000150:complications*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D012333:RNA, Messenger / Q000032:analysis; D011817:Rabbits; D014280:Triglycerides / Q000097:blood; D015854:Up-Regulation
D018932:Chemokine CCL2; D002791:Cholesterol, Dietary; D012333:RNA, Messenger; D014280:Triglycerides; D002784:Cholesterol