C. Pneumoniae and atherosclerotic plaque destabilization

描述(申请人提供)：呼吸道感染衣原体 肺炎衣原体与患肺炎的风险增加有关。 心血管疾病的发病率和死亡率。肺炎衣原体感染 加速高胆固醇血症患者动脉粥样硬化病变的发展 动物模型。然而，到目前为止，尚不清楚肺炎衣原体感染 也会导致已建立的动脉粥样硬化病变的不稳定。 不稳定的特征是坏死核的扩张和侵蚀。 中膜和纤维帽，可导致斑块破裂的过程 随后形成闭塞性血栓。细胞死亡，尤其是 巨噬细胞来源的泡沫细胞的死亡，有助于形成和 坏死核的扩张。目前还不清楚到底是什么原因导致了 动脉粥样硬化病变内细胞的死亡以及细胞保护作用 死亡可以防止斑块的不稳定。我们的初步数据显示 氧化低密度脂蛋白先积聚后感染C. 肺炎杆菌能迅速杀死大量培养的巨噬细胞。 因此，我们假设1.肺炎衣原体反复呼吸道感染 通过以下方式加速已建立的动脉粥样硬化病变的不稳定 杀死脂质负载的巨噬细胞和平滑肌细胞；2.抑制 细胞死亡将减少由脂质堆积和 肺炎衣原体感染。我们的具体目标是：1.调查 机制(S)，通过脂质负荷和感染C. 肺炎杆菌在体外杀死巨噬细胞。2：确定是否有反复感染 肺炎衣原体可增加动脉脂质负荷的速度 巨噬细胞和平滑肌细胞在体内死亡，结果：a)加速 老年人颈动脉已建立的动脉粥样硬化病变的侵蚀 载脂蛋白E基因敲除小鼠。B)严重导致破裂和出血 老年载脂蛋白E基因敲除小鼠颈动脉的动脉粥样硬化病变。 3：确定抗凋亡因子bcl-2在卵巢癌中的过度表达 白细胞减少细胞死亡和抑制：脂肪条纹的开始和 病变的进展、斑块不稳定和加速的 肺炎衣原体感染致颈动脉斑块不稳定 载脂蛋白E基因敲除小鼠的动脉。这些研究可能是第一次建立 肺炎衣原体感染加速细胞死亡和斑块失稳 从而有助于解释为什么肺炎衣原体感染与 心血管疾病死亡风险增加。

DESCRIPTION (provided by the applicant): Respiratory infection with Chlamydia pneumoniae (C. pneumoniae) is associated with an increased risk of cardiovascular disease morbidity and mortality. C. pneumoniae infection accelerates the development of atherosclerotic lesions in hypercholesterolemic animal models. However, to date it is not known whether C. pneumoniae infection also contributes to the destabilization of established atherosclerotic lesions. Destabilization is characterized by expansion of the necrotic core and erosion of the media and fibrous cap, processes that can lead to plaque rupture with subsequent formation of occlusive thrombi. Cell death, and in particular the death of macrophage-derived foam cells, contributes to the formation and expansion of the necrotic core. It is still unknown precisely what causes the death of cells within atherosclerotic lesions and whether protection from cell death will prevent plaque destabilization. Our preliminary data shows that the combination of prior accumulation of oxidized LDL followed by infection with C. pneumoniae rapidly kills a significant percentage of cultured macrophages. Thus, we hypothesize that 1. recurrent respiratory infection with C. pneumoniae accelerates the destabilization of established atherosclerotic lesions by killing lipid loaded macrophages and smooth muscle cells and 2. inhibition of cell death will reduce plaque destabilization induced by lipid accumulation and C. pneumoniae infection. Our Specific Aims are to 1: Investigate the mechanism(s) by which the combination of lipid loading and infection with C. pneumoniae kills macrophages in vitro. 2: Determine whether repeated infection with C. pneumoniae increases the rate at which lipid loaded arterial macrophages and smooth muscle cells die in vivo and as a result: A) accelerates erosion of established atherosclerotic lesions in the carotid arteries of older apo E knockout mice. B) acutely causes rupture and hemorrhage into established atherosclerotic lesions in the carotid arteries of older apo E knockout mice. 3: Determine whether the overexpression of the anti-apoptotic factor BCL-2 in leukocytes reduces cell death and inhibits: the initiation of fatty streaks and progression of the lesions, plaque destabilization, and the acceleration of plaque destabilization caused by infection with C. pneumoniae in the carotid arteries of apo E knockout mice. These studies may for the first time establish that C. pneumoniae infection accelerates cell death and plaque destabilization and thus help explain why C. pneumoniae infection is associated with an increased risk of mortality from cardiovascular disease.