MOLECULAR MECHANISMS OF CARDIOVASCULAR REMODELING INDUCED BY CHRONIC INHIBITION OF NITRIC OXIDE SYNTHESIS : ROLE OF NF-_B AND MCP-1

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Chronic inhibition of endothelial nitric oxide (NO) synthesis by the administration of N^ω-nitro-L-arginine methyl ester (L-NAME) to rats induces coronary vascular inflammation [monocytes infiltration, monocyte chemoattractant protein-1 (MCP-1) expression, and nuclear factor-kB (NF-_B) activation] in the early phase (day 3) and subsequent arteriosclerotic changes (medial thickening and perivascular fibrosis) in the late phase (day 28). MCP-1 is presumed to be a potent chemotactic factor for monocytes. NF-_B is an oxidative stress-sensitive transcription factor that regulates transcription of inflammation-promoting genes including MCP-1. However, no direct evidence for the role of NF-_B and MCP-1 in the development of such cardiovascular remodeling has been addressed in this model with chronic inhibition of NO synthesis. In the first experimental protocol, we examined the effect of in vivo transfection of cis element decoy against NF-_B to the heart. The transfection of NF-_B decoy prevented the L-NAME-induced increase in NF-_B activity, vascular inflammation and MCP-1 expression. In the second protocol, we investigated the effect of the neutralizing anti-MCP-1 antibody. Treatment with the anti-MCP-1 antibody prevented the L-NAME-induced early inflammatory changes and thus normalized coronary vascular medial thickening in the late phase. In contrast, neither NF-κB decoy transfection nor the antibody reduce the development of perivascular fibrosis, the gene expression of TGF_1, or systolic pressure overload induced by L-NAME. These results suggest that endothelium-derived NO decreases MCP-1 by suppressing oxidative stress-sensitive transcription factors such as NF-_B. The present study may provide a new aspect of how endothelium-derived NO contributes to anti-inflammatory and anti-arteriosclerotic properties of the vascular endothelium in vivo.