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

单核细胞趋化蛋白-1被认为是一种有效的单核细胞趋化因子。核因子-κB是一种氧化应激敏感的转录因子，调节包括单核细胞趋化蛋白-1在内的促炎基因的转录。然而，在这种慢性抑制NO合成的模型中，没有直接证据表明核因子-κB和单核细胞趋化蛋白-1在这种心血管重构的发展中所起的作用。在第一个实验方案中，我们检测了体内导入抗NF-κB的顺式元件诱饵对心脏的影响。转染单核细胞趋化蛋白B诱骗物可抑制L诱导的血管炎症和单核细胞趋化蛋白-1的表达，减少L对κ-κB活性的影响。在第二个方案中，我们研究了中和抗MCP-1抗体的效果。抗单核细胞趋化蛋白-1抗体治疗可阻止L诱导的早期炎症改变，从而使晚期冠脉中层增厚恢复正常。

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-κB) 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-κB 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-κB 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-κB to the heart. The transfection of NF-κB decoy prevented the L-NAME-induced increase in NF-κB 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-β1, or systolic pressure overload induced by L-NAME.These results suggest that endotheliumderived NO decreases MCP-1 by suppressing oxidative stress-sensitive transcription factors such as NF-κB.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.