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

长期抑制一氧化氮合成诱发心血管重塑的分子机制：NF-_B和MCP-1的作用

• 批准号: 11470164
• 负责人: EGASHIRA Kensuke
• 金额: $ 9.41万
• 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: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11470164/
• 关键词: gene transfer; nitric oxide; NF-κB; MCP-1; arteriosclerosis; inflammation; fibrosis; 血管内皮; アンジオテンシンII; 転写因子; monocyte chemoattractant protein-1; ケモカイン; アポE欠損マウス

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.

通过给予大鼠N^ω-硝基-L-精氨酸甲酯（L-NAME）慢性抑制内皮一氧化氮（NO）合成诱导冠状血管炎症[单核细胞浸润，单核细胞趋化蛋白-1（MCP-1）表达，和核因子-kB（NF-_B）活化]在早期阶段（第3天）和随后的动脉变化（中膜增厚和血管周围纤维化）。MCP-1被认为是单核细胞的有效趋化因子。NF-B是一种氧化应激敏感的转录因子，调节包括MCP-1在内的促炎基因的转录。然而，没有直接的证据表明NF-B和MCP-1在这种心血管重构的发展中的作用已经在这个模型中与NO合成的慢性抑制中得到解决。在第一个实验方案中，我们检查了针对NF-B的顺式元件诱饵体内转染到心脏的效果。转染NF-B decoy可抑制L-NAME诱导的NF-B活性升高、血管炎症和MCP-1表达。在第二个方案中，我们研究了中和抗MCP-1抗体的作用。用抗MCP-1抗体治疗防止了L-NAME诱导的早期炎症变化，从而使晚期冠状动脉血管中膜增厚正常化。与此相反，NF-κB诱饵转染和抗体都不能减少L-NAME诱导的血管周围纤维化、TGF-1基因表达或收缩压超负荷的发生。这些结果表明，内皮源性NO通过抑制氧化应激敏感的转录因子如NF-B降低MCP-1。本研究可能提供了一个新的方面，如何内皮源性NO有助于抗炎和抗动脉炎的血管内皮细胞在体内的属性。

项目成果

Usui Mなど.: "Pathogenic role og oxidative stress in vascular angiotensin-conberting enzyme activation in long-term blockade of nitric oxide synthesis in rats."Hypertension. 34. 546-551 (1999)

Usui M 等人：“氧化应激在大鼠长期阻断一氧化氮合成中血管血管紧张素转换酶激活的致病作用。”高血压。 34. 546-551 (1999)

Kataoka C, Egashira K, et al.: "Important Role of Rho-kinase in the Pathogenesis of Cardiovascular Inflammation and Remodeling Induced by Long-Term Blockade of Nitric Oxide Synthesis in Rats"Hypertension. 39. 245-250 (2002)

Kataoka C、Egashira K 等人：“Rho 激酶在大鼠长期阻断一氧化氮合成诱导的心血管炎症和重塑发病机制中的重要作用”高血压。

Usui M,Egashira K, et al.: "Important role of local angiotensin II activity mediated via type 1 receptor in the pathogenesis of cardiovascular inflammatory changes induced by blockade of nitric oxide synthesis.2000;101:305-310"Circulation. 101. 305-310 (2

Usui M、Egashira K 等人：“通过 1 型受体介导的局部血管紧张素 II 活性在阻断一氧化氮合成诱导的心血管炎症变化的发病机制中的重要作用。2000；101：305-310”循环。

Ni WH, Egashira K, et al.: "Anti-inflammatory and Anti-arteriosclerotic Actions of HMG-CoA Reductase Inhibitors in a Rat Model of Chronic Inhibition of Nitric Oxide Synthesis"Circulation Research. 189. 415-421 (2001)

Ni WH、Egashira K 等人：“HMG-CoA 还原酶抑制剂在慢性抑制一氧化氮合成的大鼠模型中的抗炎和抗动脉硬化作用”循环研究。

Zhao Q, Egashira K, et al.: "Vascular Endothelial Growth Factor is Necessary in the Development of Arteriosclerosis by Recruiting/Activating Monocytes in a Rat Model of Long-Term Inhibition of Nitric Oxide Synthesis"(2001)

赵 Q、Egashira K 等人：“在长期抑制一氧化氮合成的大鼠模型中，通过招募/激活单核细胞，血管内皮生长因子对于动脉硬化的发展是必要的”(2001)