C. Pneumoniae and atherosclerotic plaque destabilization

描述（由申请方提供）：衣原体呼吸道感染 pneumoniae（C.肺炎）与以下风险增加相关： 心血管疾病发病率和死亡率。C.肺炎菌感染 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，还不知道C。肺炎菌感染 也有助于已形成的动脉粥样硬化病变的不稳定。 失稳的特征是坏死核心的扩张和侵蚀 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，特别是 巨噬细胞衍生的泡沫细胞的死亡，有助于形成和 坏死核心的扩张目前还不清楚是什么原因导致了 动脉粥样硬化病变内的细胞死亡以及是否有细胞保护 死亡将阻止斑块不稳定。初步数据显示， 结合氧化低密度脂蛋白的先前积累以及C. 肺炎杆菌迅速杀死显著百分比的培养的巨噬细胞。 因此，我们假设1。反复呼吸道感染C.肺炎 加速已形成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，以及2.抑制 细胞死亡将减少由脂质积累诱导的斑块不稳定， C.肺炎感染。我们的具体目标是1：调查 脂质负荷和C. 肺炎杆菌在体外杀死巨噬细胞。2：确定是否反复感染 梭肺炎增加了脂质负荷动脉 巨噬细胞和平滑肌细胞在体内死亡，结果：A）加速 老年人颈动脉中已建立的动脉粥样硬化病变的侵蚀 apo E基因敲除小鼠。B）急性引起破裂和出血， 老年载脂蛋白E基因敲除小鼠颈动脉粥样硬化病变。 3：确定抗凋亡因子BCL-2在细胞中的过表达是否与细胞凋亡相关。 白细胞减少细胞死亡和抑制：脂肪条纹的开始， 病变的进展、斑块不稳定和 C.感染引起的斑块不稳定。颈动脉肺炎 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 梭肺炎感染加速细胞死亡和斑块不稳定 这有助于解释为什么C.肺炎感染与 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.