Investigation of mechanism on radiation-induced atheroma

癌症患者的放射治疗可能导致受累大动脉的动脉粥样硬化，并且病变包含大量过氧化物酶体增殖物激活受体γ（PPARγ）阳性巨噬细胞。PPARγ调节成纤维细胞中的脂肪形成、单核细胞/巨噬细胞分化和活化以及凋亡。在这里，我们证明，电离辐射（IR）增加人单核细胞U 937细胞的胆固醇摄取，通过机制涉及CD 36清道夫受体。U 937细胞摄取胆固醇与核内PPARγ的积累增加有关，但与PPARα无关，并激活了PPARγ依赖的转录活性。而PPARγ激动剂曲格列酮则抑制IR诱导的U937细胞胆固醇摄取。重要的是，通过siRNA阻断PPARγ可增强U 937细胞的胆固醇摄取，而曲格列酮处理不会抑制去除PPARγ的U 937细胞的胆固醇摄取。人单核细胞对IR的反应也表现为PPARγ蓄积和胆固醇摄取。这些结果提示，PPARγ在IR后动脉粥样硬化的形成中起抑制作用，可能为IR治疗癌症患者动脉粥样硬化的预防提供一种可能的策略。

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.