Development of highly-sensitive evaluation method of endothelial cell function and early diagnostic procedure of atherosclerosis by positron emission tomography

正电子发射断层扫描高灵敏评价内皮细胞功能和动脉粥样硬化早期诊断方法的开发

• 批准号: 10557050
• 负责人: ITOH Hiroshi
• 金额: $ 7.3万
• 依托单位: KYOTO 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-10557050/
• 关键词: Endothelial Cells; Nitric Oxide (NO); NO synthase (NOS); Positron Emission Tomography (PET); Atherosclerosis; Calcium Ionophore; TGF-β; 一酸化窒素; カルシウム

Early detection of atherosclerosis complicated with hypertension, diabetes mellitus or hyperlipidemia is clinically very crucial. Diagnostic procedure of atherosclerosis so far have many problems; for example, they are very insensitive and detect only advanced lesions or they are very invasive and require high technique. This research project aims at establishment of a new diagnostic method of atherosclerosis to evaluate the decreased activity of nitric oxide (NO) synthase (NOS) in endothelial cells by utilizing PET.We obtained the following results:1. We succeeded in the labeling of L-NAME, the NOS inhibitor by ィイD13ィエD1H and ィイD111ィエD1C.2. Using ィイD13ィエD1H-L-NAME, we demonstrated that uptake of L-NAME by endothelial cells can reflect the activity of NO production (NOS activity) in vitro.3. Using ィイD111ィエD1C-L-NAME, we succeeded in in vitro PET imaging of endothelial cells.4. Ionomycin, the calcium ionohore augmented the uptake of ィイD111ィエD1C-L-NAME and we could detect more intense imaging of endothelial cells treated with ionomycin compared with the control.These results suggest that PET imaging using labeled L-NAME can be the evaluation method of endothelial function (NO production). Towards the in vivo application of our method, search for metabolically more stable L-NAME-related compounds and their labeling for PET imaging are required.

早期发现动脉粥样硬化合并高血压、糖尿病或高脂血症在临床上非常重要。动脉粥样硬化的诊断程序至今仍存在许多问题，例如，它们非常不敏感，只能检测到晚期病变，或者它们非常侵入性，需要高技术。本研究旨在建立一种新的动脉粥样硬化诊断方法，利用PET技术检测血管内皮细胞一氧化氮合酶（NOS）活性的降低。我们成功地将NOS抑制剂L-NAME标记为荧光素D13荧光素D1 H和荧光素D111荧光素D1C。利用荧光素D13荧光素D1 H-L-NAME，我们证明了内皮细胞摄取L-NAME可以反映体外NO产生的活性（NOS活性）.利用荧光染料D111荧光染料D1C-L-NAME成功地进行了内皮细胞的体外PET显像.结果表明，与对照组相比，离子霉素（Ionomycin）可增强内皮细胞对D111受体D1C-L-NAME的摄取，并可检测到更强的显像，提示标记L-NAME的PET显像可作为评价内皮细胞功能（NO生成）的方法。对于我们的方法的体内应用，需要寻找代谢更稳定的L-NAME相关化合物及其标记用于PET成像。

项目成果

H.Itoh et al.: "Vascular strss response and endothelial vasoactive factors for vascular remodeling"Diabetes Res. Clin. Pr.. 45. 83-88 (1999)

H.Itoh 等人：“血管应激反应和内皮血管活性因子对血管重塑”糖尿病研究。

M.Harada et al.: "Interaction of myocyles and nonmyocytes is necessary for mechanical stretch induce ANP/BNP production in cardiocyte culture"J. Cardiovasc. Pharmacol.. 31 SUPPL.1. (1998)

M.Harada 等人：“肌细胞和非肌细胞的相互作用对于机械拉伸诱导心肌细胞培养物中 ANP/BNP 的产生是必要的”J.

M.Inoue et al.: "Vascular endothelial growth factor (VEGF)exprssion in human coronary atherosclerotic lesions : Possible pathophysiological significance of VEGF in progression of athrosclerosis"Circulatin. 98. 2108-2116 (1998)

M.Inoue 等人：“人冠状动脉粥样硬化病变中的血管内皮生长因子 (VEGF) 表达：VEGF 在动脉粥样硬化进展中可能的病理生理学意义”循环。

T-H.Chum et al.: "Oxidative stress augments secretion of endothelium-derived relaxing peptides, C-type natriuretic peptide and adrenamedullin"J. Hyfpertens.. (in press). (2000)

T-H.Chum 等人：“氧化应激增强内皮源性松弛肽、C 型利尿钠肽和肾上腺髓质素的分泌”J.

Y.Miyamoto et al.: "Endothelial nitric oxide synthase gene is positively associated with essential hypertension." Hypertension. 32. 3-8 (1998)

Y.Miyamoto 等人：“内皮一氧化氮合酶基因与原发性高血压呈正相关。”