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

我们最近发现，L-硝基-L-精氨酸甲酯(NAME-NAME)慢性抑制一氧化氮(NO)合成可诱导大鼠心脏单核细胞浸润和单核细胞趋化蛋白-1(MCP-1)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，而单核细胞趋化因子1是单核细胞的主要趋化因子。核因子-kB(NF-kappaB)被认为是一种重要的转录因子，可诱生MCP-1等炎性细胞因子。血管紧张素II在体外可激活趋化作用和核因子-kappaB。在本研究中，我们验证了血管紧张素Ⅱ介导这种炎症变化的假说，以及通过抑制NO合成而诱导的大鼠心脏核因子-kappaB的激活。在L给药第3天，我们观察到单核细胞对冠状动脉和心肌间质的浸润、单核细胞趋化蛋白-1的表达和核因子-kappaB的活性显著增加。随着这些变化，血管超氧阴离子的产生也增加。应用血管紧张素II 1型受体拮抗剂可阻止L所致的上述改变，提示内源性血管紧张素II在介导炎症变化中起重要作用，而应激、核因子-kappaB活化和单核细胞趋化蛋白-1的表达可能参与炎症的发生。结果还表明，血管紧张素II受体阻断在早期动脉硬化和/或动脉粥样硬化中可能有有益的效果。

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.