molecular mechanisms of vascular remodeling induced by blockade of nitric oxide synthesis

我们最近发现，诺米加-硝基- l -精氨酸甲酯（L-NAME）对一氧化氮（NO）合成的慢性抑制可诱导大鼠心脏中单核细胞浸润和单核细胞趋化蛋白-1 （MCP-1）的表达。然而，这些变化的机制尚不清楚。单核细胞迁移到血管中是导致动脉粥样硬化的关键早期事件，MCP-1是单核细胞的主要趋化因子。核因子- kb （NF-kappaB）被认为是诱导炎性细胞因子如MCP-1的重要转录因子。血管紧张素II已被证明在体外激活趋化性和nf - κ b。在本研究中，我们验证了angiotesin II通过抑制NO合成介导大鼠心脏炎症变化和NF-kappaB激活的假设。我们观察到，在给药第3天，冠状血管和心肌间质区单核细胞浸润、MCP-1表达和NF-kappaB活性显著增加。随着这些变化，血管超氧阴离子的产生也增加。用血管紧张素II型1受体拮抗剂治疗可防止L-NAME引起的所有这些变化。我们目前的研究结果表明，内源性血管紧张素II在该模型中介导炎症变化中起重要作用，而氧化应激、NF-kappaB激活和MCP-1表达可能参与了炎症的发病机制。结果还表明，血管紧张素II受体阻断可能对早期动脉硬化和/或动脉粥样硬化有有益的作用。

We have recently showed that chronic inhibition of nitric oxide (NO) synthesis by Nomega-nitoro-L-arginine methy ester (L-NAME) induces a marked monocyte infiltration and monocyte chemoattractant protein-1 (MCP-1) expression in rat hearts. However, the mechanisms of these changes are not known. The migration of monocytes into the blood vessels is a critical early event leading to atherosclrosis and MCP-1 is a major chemokine for monocytes. Nuclear factor-KB (NF-kappaB) is believed to be an important transcriptional factor that induces inflammatory cytokines such as MCP-1. Angiotensin II has been shown to activate chemotaxis and NF-kappaB in vitro.In the present study, we tested the hypothesis that angiotesin II mediates such inflammatory changes and NF-kappaB activation in rat hearts induced by inhibition of NO synthesis. We observed a marked increases in monocyte infiltrarion into coronary vessels and myocardial interstitial areas, MCP-1 expression and NF-kappaB activity during on the 3rd day of L-NAME administation. Along eith these changes, vascular superoxide anion production is also increased. Treatment with an angiotensin II type 1 receotor antagonist prevented all of these changes induced by L-NAME administration.Our present results sugest that endogenous angiotensin II pleays an important role in mediating inflammatory changes in this model and that okidative stress, NF-kappaB activation and MCP-1 expression may be involved in the pathogenesis of the inflammation. Results also suggest that angiotenisin II receptor blockade may have beneficial effects in early arteriosclerosis and/or atheroscleorsis.