The mechanism of atherosclerotic plaque disruption in experimental animal model. The concept of the involvement of cathepsins.

实验动物模型中动脉粥样硬化斑块破坏的机制。

• 批准号: 21700447
• 负责人: SASAKI Takeshi
• 金额: $ 2.75万
• 依托单位: Hamamatsu University School of Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Young Scientists (B)
• 财政年份: 2009
• 资助国家: 日本
• 起止时间: 2009 至 2010
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21700447/
• 关键词: プラーク破綻; カテプシン; アンギオテンシン1型受容体; 細胞外マトリックス; マクロファージ; 動脈硬化症; 実験動物モデル; imaging mass spectrometry; 炎症細胞

Although it has been suggested that the renin-angiotensin (RA) system and cathepsins contribute to the development and vulnerability of atherosclerotic plaque, the interaction of the RA system and cathepsins is unclear. Thus, we investigated the effects of an angiotensin II type 1 receptor (AT1) antagonist, olmesartan, on the levels of cathepsins in brachiocephalic atherosclerotic plaque and plaque stabilization in apolipoprotein E (apoE)-deficient mice receiving a high-fat diet. Under a high fat diet, treatment with olmesartan (3 mg/kg per day) maintained collagen and elastin at high levels and attenuated the plaque development and cathepsin S (Cat S) level in the atherosclerotic plaque of apoE-deficient mice. The administration of olmesartan suppressed the accumulation of macrophages in plaque. Immunoreactivities of Cat S and AT1 were observed in macrophages. The amount of Cat S mRNA and the macrophage-mediated collagenolytic and elastolytic activities in cultured macrophages were increased by exposure to angiotensin II (Ang II), and these effects were diminished by olmesartan and the NADPH-oxidase inhibitor apocynin. These results suggested that Cat S derived from macrophages is involved in the mechanisms of atherosclerotic plaque vulnerability, and AT1 blocker maintained the plaque stabilization alongside the suppression of Cat S and macrophage activities.

虽然已经表明，肾素-血管紧张素（RA）系统和组织蛋白酶有助于动脉粥样硬化斑块的发展和脆弱性，RA系统和组织蛋白酶的相互作用尚不清楚。因此，我们研究了血管紧张素II 1型受体（AT 1）拮抗剂奥美沙坦对接受高脂饮食的载脂蛋白E（apoE）缺陷小鼠头臂动脉粥样硬化斑块中组织蛋白酶水平和斑块稳定性的影响。在高脂饮食下，奥美沙坦（3 mg/kg/天）治疗可维持高水平的胶原蛋白和弹性蛋白，并减弱apoE缺陷小鼠动脉粥样硬化斑块中的斑块发展和组织蛋白酶S（Cat S）水平。奥美沙坦给药可抑制斑块中巨噬细胞的积聚。巨噬细胞中有Cat S和AT 1的免疫反应。Cat S mRNA的量和巨噬细胞介导的胶原溶解和弹性蛋白溶解活性在培养的巨噬细胞中增加暴露于血管紧张素II（Ang II），这些影响被奥美沙坦和NADPH氧化酶抑制剂夹竹桃苷减弱。这些结果表明，来源于巨噬细胞的Cat S参与了动脉粥样硬化斑块易损性的机制，AT 1阻断剂在抑制Cat S和巨噬细胞活性的同时维持了斑块的稳定性。

项目成果

Imaging Mass Spectrometry Reveals Unique Lipid Distribution in Primary Varicose Veins

• DOI: 10.1016/j.ejvs.2010.08.001
• 发表时间: 2010-11-01
• 期刊: EUROPEAN JOURNAL OF VASCULAR AND ENDOVASCULAR SURGERY
• 影响因子: 5.7
• 作者: Tanaka, H.;Zaima, N.;Setou, M.
• 通讯作者: Setou, M.

Exercise Training Stimulates Neovascularization in Response to Ischemia via HIF-1α-VEGF- mediated Activation of MMP-2 in Advanced Age.

老年运动训练通过 HIF-1α-VEGF 介导的 MMP-2 激活刺激新生血管形成以应对缺血。

• 发表时间: 2009
• 作者: Xian Wu Cheng;Masafumi Kuzuya;Lina Hu;Haizhen Song;Aiko Inoue;Kae Nakamura;Takeshi Sasaki;Kenji Okumura;Toyoaki Murohara
• 通讯作者: Toyoaki Murohara

AT1 blockade attenuates atherosclerotic plaque destabilization accompanied by the suppression of cathepsin S activity in apoE-deficient mice.

• DOI: 10.1016/j.atherosclerosis.2009.12.031
• 发表时间: 2010-06
• 期刊: Atherosclerosis
• 影响因子: 5.3
• 作者: Takeshi Sasaki;M. Kuzuya;Kae Nakamura;X. Cheng;Taiju Hayashi;Haizhen Song;Lina Hu;K. Okumura;T. Murohara;A. Iguchi;Kohji Sato

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Angiotensin type 1 receptor blocker reduces intimal neovascularization and plaque growth in apolipoprotein E-deficient mice.

• DOI: 10.1161/hypertensionaha.110.168385
• 发表时间: 2011-05
• 期刊: Hypertension (Dallas, Tex. : 1979)
• 作者: Cheng XW;Song H;Sasaki T;Hu L;Inoue A;Bando YK;Shi GP;Kuzuya M;Okumura K;Murohara T
• 通讯作者: Murohara T