: 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.
