Abstract
Background:
Chronic inhibition of endothelial nitric oxide (NO) synthesis by the administration of N:(omega)-nitro-L-arginine methyl ester (L-NAME) to rats induces early vascular inflammatory changes (monocyte infiltration into coronary vessels and monocyte chemoattractant protein-1 [MCP-1] expression) as well as subsequent arteriosclerosis (medial thickening and perivascular fibrosis) and cardiac fibrosis. However, the role of MCP-1 in this process is not known.
Methods and results:
We investigated the effect of a specific monoclonal anti-MCP-1 neutralizing antibody in rats treated with L-NAME to determine the role of monocytes in the regulation of cardiovascular remodeling. We found increased expression of MCP-1 mRNA in vascular endothelial cells and monocytes in inflammatory lesions. Cotreatment with an anti-MCP-1 antibody, but not with control IgG, prevented the L-NAME-induced early inflammation and reduced late coronary vascular medial thickening. In contrast, the anti-MCP-1 antibody did not decrease the development of perivascular fibrosis, the expression of transforming growth factor (TGF)-beta(1) mRNA, or systolic pressure overload induced by L-NAME administration.
Conclusions:
These results suggest that MCP-1 is necessary for the development of medial thickening as well as monocyte recruitment. In contrast, the pathogenesis of fibrosis may involve other factors, such as TGF-beta(1).
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Monoclonal / pharmacology
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Blood Pressure / drug effects
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Cell Division / drug effects
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Chemokine CCL2 / antagonists & inhibitors
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Chemokine CCL2 / metabolism*
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Chemokine CCL2 / pharmacology
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Chronic Disease
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Collagen / biosynthesis
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Collagen / genetics
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Coronary Artery Disease / chemically induced
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Coronary Artery Disease / metabolism*
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Coronary Artery Disease / pathology
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Dermis / drug effects
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Dermis / pathology
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Fibrosis / pathology
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Inflammation / chemically induced
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Inflammation / pathology
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Male
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Monocytes / cytology
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Monocytes / drug effects
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Myocardium / metabolism
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NG-Nitroarginine Methyl Ester
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Nitric Oxide Synthase / antagonists & inhibitors*
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Nitric Oxide Synthase / metabolism
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Peptidyl-Dipeptidase A / metabolism
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RNA, Messenger / biosynthesis
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Rats
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Rats, Inbred WKY
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Recombinant Proteins / antagonists & inhibitors
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Recombinant Proteins / metabolism
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Recombinant Proteins / pharmacology
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Transforming Growth Factor beta / biosynthesis
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Transforming Growth Factor beta / genetics
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Transforming Growth Factor beta1
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Ventricular Remodeling
Substances
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Antibodies, Monoclonal
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Chemokine CCL2
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RNA, Messenger
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Recombinant Proteins
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Tgfb1 protein, rat
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Transforming Growth Factor beta
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Transforming Growth Factor beta1
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Collagen
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Nitric Oxide Synthase
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Peptidyl-Dipeptidase A
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NG-Nitroarginine Methyl Ester