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

阻断一氧化氮合成诱导血管重塑的分子机制

• 批准号: 08457212
• 负责人: EGASHIRA Kensuke
• 金额: $ 4.93万
• 依托单位: KYUSHU UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08457212/
• 关键词: nitric oxide; angiotensin-converting enzyme; angiotensin II; thrombosis; atherosclerosis; oxidative stress; macrophages; アンジオテンシンII受容体; 血管リモデリング; 内皮細胞; 狭心症; レニン-アンギオテンシン系; アンギオテンシン変換酵素

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.

我们最近发现，长期抑制一氧化氮（NO）合成的N-硝基-L-精氨酸甲酯（L-NAME）诱导大鼠心脏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。单核细胞向血管中的迁移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-κ B（NF-κ B）被认为是诱导炎症细胞因子如MCP-1的重要转录因子。血管紧张素II已被证明激活趋化性和NF-κ B在体外，在本研究中，我们测试的假设，即血管紧张素II介导的这种炎症变化和NF-κ B的激活在大鼠心脏诱导的抑制NO的合成。在L-NAME给药的第3天，我们观察到冠状动脉血管和心肌间质中的单核细胞浸润、MCP-1表达和NF-κ B活性显著增加。沿着这些变化，血管超氧阴离子的产生也增加。血管紧张素Ⅱ 1型受体拮抗剂治疗可阻止L-NAME诱导的上述变化，提示内源性血管紧张素Ⅱ在该模型中介导炎症变化中起重要作用，促炎性应激、NF-κ B活化和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受体阻滞剂可能对早期动脉硬化和/或动脉粥样硬化有有益的影响。

项目成果

Takemoto M,et al: "Chronic angiotensin-convertring enzyme inhibition and angiotensin II type 1 receptor blockade.Effects on cardiovascular remodeling in rats induced by the long-term blockade of・・・・" Hypertension. 30・6. 1621-1627 (1997)

Takemoto M 等人：“慢性血管紧张素转换酶抑制和血管紧张素 II 1 型受体阻断。长期阻断……对大鼠心血管重塑的影响” 高血压。 1621-1627。 ）

Ichiki T,et al.: "Downregulation of angiotonsin II type 1 receptor gene transcription by nitric oxide" Hypertension. in press.

Ichiki T 等人：“一氧化氮下调血管紧张素 II 1 型受体基因转录”高血压。

Takemoto M, et al: "Chronic angiotensin-convertring enzyme inhibition and angiotensin II type 1 receptor blockade.Effects on cardiovascular remodeling in rats induced by the long-term blockade of・・・・" Hypertension. 30・6. 1621-1627 (1997)

Takemoto M 等人：“慢性血管紧张素转换酶抑制和血管紧张素 II 1 型受体阻断。长期阻断……对大鼠心血管重塑的影响” 高血压。 1621-1627。 ）

Takemoto M Egashira K Usui M Numaguchi K Tomita H Tsutsui H Shimokawa H Sueishi K Takeshita A: "Important role of tissue angiotensin-converting enzyme activity in the pathogenesis of coronary vascular and myocardial structual changes induced by longterm b

Takemoto M Egashira K Usui M Numaguchi K Tomita H Tsutsui H Shimokawa H Sueishi K Takeshita A：“组织血管紧张素转换酶活性在长期b引起的冠状血管和心肌结构变化的发病机制中的重要作用

Takemoto M et al.: "Chronic angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor blockade. Effects on cardiovascular remodeling in rats induced by the long-term blockade of nitric oxide synthesis" Hypertension. 30. 1621-1627 (1997)

Takemoto M 等人：“慢性血管紧张素转换酶抑制和血管紧张素 II 1 型受体阻断。长期阻断一氧化氮合成对大鼠心血管重塑的影响”高血压。