Protective Role of Peroxisome Proliferator-Activated Receptor-γ in the Development of Intracranial Aneurysm Rupture.
Protective Role of Peroxisome Proliferator-Activated Receptor-γ in the Development of Intracranial Aneurysm Rupture.
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DOI：
10.1161/strokeaha.114.007722
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发表时间：
2015-06
期刊：
影响因子：
8.3
通讯作者：
Hashimoto T
中科院分区：
文献类型：
--
作者：
Shimada K;Furukawa H;Wada K;Korai M;Wei Y;Tada Y;Kuwabara A;Shikata F;Kitazato KT;Nagahiro S;Lawton MT;Hashimoto T
炎症正在成为颅内动脉瘤病理生理学的关键组成部分。过氧化物酶体增殖物激活受体-γ（过氧化物酶体增殖物激活受体γ）是一种核激素受体，其激活调节炎症的各个方面。利用小鼠颅内动脉瘤模型，我们研究了PPARγ在颅内动脉瘤破裂发展中的潜在作用。PPARγ激动剂吡格列酮（PGZ）显著降低了破裂动脉瘤的发生率和破裂率，而不影响动脉瘤（未破裂动脉瘤和破裂动脉瘤）的总发生率。PPARγ拮抗剂（GW 9662）可阻断PGZ的保护作用。PGZ对巨噬细胞PPARγ缺乏的小鼠无保护作用。PGZ治疗降低了主要由脑动脉中的巨噬细胞产生的炎性细胞因子（单核细胞趋化因子-1、白细胞介素-1和白细胞介素-6）的mRNA水平。PGZ处理可减少M1巨噬细胞向脑动脉的浸润，降低M1/M2比值。吞噬巨噬细胞显著降低破裂率。我们的数据表明，激活巨噬细胞的过氧化物酶体增殖物激活受体γ保护免受囊肿破裂的发展。炎性细胞中的PPARγ可能是预防膀胱破裂的潜在治疗靶点。
Inflammation is emerging as a key component of the pathophysiology of intracranial aneurysms. Peroxisome proliferator-activated receptor-γ (PPARγ) is a nuclear hormone receptor of which activation modulates various aspects of inflammation. Using a mouse model of intracranial aneurysm, we examined the potential roles of PPARγ in the development of rupture of intracranial aneurysm. A PPARγ agonist, pioglitazone (PGZ), significantly reduced the incidence of ruptured aneurysms and the rupture rate without affecting the total incidence aneurysm (unruptured aneurysms and ruptured aneurysms). PPARγ antagonist (GW9662) abolished the protective effect of PGZ. The protective effect of PGZ was absent in mice lacking macrophage PPARγ. PGZ treatment reduced mRNA levels of inflammatory cytokines (monocyte chemoattractant factor-1, interleukin-1, and interleukin-6) that are primarily produced by macrophages in the cerebral arteries. PGZ treatment reduced the infiltration of M1 macrophage into the cerebral arteries and the macrophage M1/M2 ratio. Depletion of macrophages significantly reduced the rupture rate. Our data showed that the activation of macrophage PPARγ protects against the development of aneurysmal rupture. PPARγ in inflammatory cells may be a potential therapeutic target for the prevention of aneurysmal rupture.