Investigation of mechanism on radiation-induced atheroma

放射线引起的动脉粥样硬化机制研究

• 批准号: 15591997
• 负责人: KATAYAMA Ikuo
• 金额: $ 1.92万
• 依托单位: NAGASAKI UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15591997/
• 关键词: ionizing radiation; atherosclerosis; macrophage; PPARγ; atheroselerosis

Radiation therapy in cancer patients may results in atherosclerosis of involved large arteries, and the lesion contains a large number of peroxisome proliferator activated receptor γ(PPARγ)-positive macrophages. PPARγ regurates adipogenesis in fibroblasts, monocyte/macrophage differentiation and activation, and apoptosis. Here we demonstrated that ionizing radiation(IR) increased cholesterol uptake by human monocyic U 937 cells, through the mechanism involving CD 36 scavenger receptors. The cholesterol uptake by U 937 cells was associated with enhanced nuclear accumulation of PPARγ, but not PPARα, and activated PPARγ-dependent transcriptional activity. However, PPARγ agonist troglitazone inhibited the IR-induced cholesterol uptake in U 937 cells. Importantly, PPARγ ablation by siRNA enhanced cholesterol uptake in U 937 cells, and troglitazone treatment did not inhibited the uptake in the PPARγ-depleted U 937 cells. In response to IR, human monocytes also showed PPARγ accumulation and cholesterol uptake. These results suggests that PPARγ plays an inhibitory role in the formation of atherosclerosis in response to IR and may provide a possible strategy for prevention of atherosclerosis in cancer patients treated with IR.

肿瘤患者放射治疗可导致受累大动脉的动脉粥样硬化，病变内含有大量过氧化物酶体增殖物激活受体γγ阳性巨噬细胞。PPARγ可促进成纤维细胞的脂肪生成、单核/巨噬细胞的分化和激活以及细胞的凋亡。在这里，我们证明了电离辐射(IR)通过涉及CD36清道夫受体的机制增加了人单核细胞U 937细胞对胆固醇的摄取。U937细胞对胆固醇的摄取与PPARγ的核聚集有关，而与PPARα的核积聚无关，并激活了PPARγ依赖的转录活性。但PPARγ激动剂曲格列酮可抑制IR诱导的U937细胞胆固醇摄取。重要的是，用小干扰RNA去除PPARγ可增加U937细胞对胆固醇的摄取，曲格列酮处理不抑制PPARγ缺失的U937细胞对胆固醇的摄取。作为对IR的反应，人单核细胞也表现出PPARγ积聚和胆固醇摄取。这些结果表明，PPARγ在IR后动脉粥样硬化的形成中起抑制作用，可能为IR治疗的癌症患者预防动脉粥样硬化提供一种可能的策略。