Development of quantitative analysis method of the atherosclerotic lesions in gene targeted mice

基因靶向小鼠动脉粥样硬化病变定量分析方法的建立

• 批准号: 10557027
• 负责人: TAKAHASHI Kiyoshi
• 金额: $ 1.73万
• 依托单位: Kumamoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10557027/
• 关键词: atherosclerosis; scavenger receptors; gene targeted mice; foam cell formation; morphometry; macrophages; image analysis equipment; anti-oxidant; 泡抹細胞化; マウス

One of the most reliable methods for the quantitative analysis of atherosclerotic lesions is direct measurement of the lesion size on tissue sections. In this study, we selected the cross-sections through the aortic valve and ascending aorta where the atherosclerosis occurs at very early stage. Using the aortic valve as a marker, the place of the sectioning is easily oriented. In practice, the four slices crossing aortic valve and ascending aorta were selected, and the area of atherosclerosis in each section was measured by the image analysis microscope system.Using this method, it was quantitatively proven that the progress of the atherosclerosis in LDL receptor deficient mice was suppressed in the absence of macrophage scavenger receptor (MSR). Other scavenger receptors than MSR such as CD36, MARCO receptor, and CD68/Macrosialin were considered to concern in the lipid uptake of the macrophages at the remaining lesion. This method was also available for the evaluation of anti-atherosclerosis drugs. The measurement showed that a newly developed antioxidant (BO-653) was effective to reduce the atherosclerotic lesion size in ApoE deficient mice.Though the introduction of the present image analysis microscope system enabled us to carry out the quantitative analysis of the atherosclerosis very conveniently, it has been shown recently that the nature of the atheroma is more concerned to the crisis of the acute coronary syndrome than the degree of stenosis of the artery. Soft atheroma which is rich in macrophages is easy to cause atheroma rupture. From this fact, for the evaluation of the atherosclerosis lesion, it was not sufficient to compare the lesion size only, and it seemed to be important to evaluate the pathological nature of the atheroma itself. This seemed to be the future research subject.

动脉粥样硬化病变定量分析的最可靠方法之一是直接测量组织切片上的病变大小。在这项研究中，我们选择了横截面通过主动脉瓣和升主动脉粥样硬化发生在非常早期的阶段。使用主动脉瓣作为标记，切片的位置很容易定位。在实验中，选取了横跨主动脉瓣和升主动脉的4个切片，用图像分析显微镜系统测量了每个切片中动脉粥样硬化的面积，定量证明了巨噬细胞清道夫受体（MSR）缺乏抑制了LDL受体缺陷小鼠动脉粥样硬化的进展。认为MSR以外的其他清道夫受体（如CD 36、MARCO受体和CD 68/Macrosialin）与剩余病变处巨噬细胞的脂质摄取有关。该方法也可用于抗动脉粥样硬化药物的评价。实验结果表明，一种新开发的抗氧化剂BO-653对ApoE基因缺陷小鼠动脉粥样硬化病变有明显的缩小作用。虽然目前图像分析显微镜系统的引入使我们能够非常方便地进行动脉粥样硬化的定量分析，近年来研究表明，动脉粥样硬化的性质与急性冠状动脉综合征的危象比动脉狭窄的程度更相关。富含巨噬细胞的软质动脉粥样硬化易导致动脉粥样硬化破裂。从这一事实来看，对于动脉粥样硬化病变的评价，仅比较病变大小是不够的，评价动脉粥样硬化本身的病理性质似乎很重要。这似乎是未来的研究课题。

项目成果

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Kaikita K 等人：“冠状动脉粥样硬化中组织因子和组织因子途径抑制剂的共定位”J Pathol。

Sakaguchi H et al.: "Role of macrophage scavenger receptors in diet-induced atherosclerosis" Lav Invest. 78. 423-434 (1998)

Sakaguchi H 等人：“巨噬细胞清道夫受体在饮食引起的动脉粥样硬化中的作用”Lav Invest。

Sakaguchi H et al.: "Role of macrophage scavenger receptors in diet-induced atherosclerosis in mice" Lab Invest. 78. 423-434 (1998)

Sakaguchi H 等人：“巨噬细胞清道夫受体在饮食诱导的小鼠动脉粥样硬化中的作用”实验室投资。

Hakamata,H et al.: "The very low-and intermediate-density lipoprotein fraction isolated from apolipoprotein E-knockout mice transforms macrophages to foam cells through an apolipoprotein E-independent pathway" Biochemistry. 37. 13720-13727 (1998)

Hakamata, H 等人：“从载脂蛋白 E 敲除小鼠中分离出的极低和中密度脂蛋白组分通过载脂蛋白 E 独立途径将巨噬细胞转化为泡沫细胞”生物化学。

Cynshi O et al.: "Antiatherogenic effects of the antioxidant BO-653 in three different animal models" Proc Natl Acad Sci,USA. 95. 10123-10128 (1998)

Cynshi O 等人：“抗氧化剂 BO-653 在三种不同动物模型中的抗动脉粥样硬化作用”Proc Natl Acad Sci，美国。