| Summary: | Strong clinical and experimental evidence has suggested the involvement of Chlamydia pneumoniae (C. pneumoniae) in the development of atherosclerosis. However, the direct role of C. pneumoniae infection in vascular remodelling processes in the absence of a host immune response remains undetermined.
To study the direct effect of this pathogen within the arterial wall, we developed a novel ex vivo porcine coronary artery model that supported bacterial growth for up to two weeks in culture. Employing this approach, we demonstrated that C. pneumoniae infection could alter vascular functions parameters, including endothelial-dependent relaxation responses. This impairment was associated with a decrease in eNOS expression and increased oxidative stress, changes that are also noted in atherosclerotic plaques. We further demonstrated that C. pneumoniae infection initiates medial thickening via vascular smooth muscle cell (VSMC) proliferation. This proliferative response was associated with an increase in expression of endogenous heat shock protein 60 (Hsp60) and alterations in nuclear protein import machinery. Additionally, C. pneumoniae infection and Hsp60 overexpression in primary VSMCs resulted in alteration in nuclear protein import parameters leading to the cell proliferation. Using a rabbit atherosclerotic model, we demonstrated that Hsp60 is induced during atherosclerotic lesion growth and correlated with both the proliferative status and the expression of protein involved in nuclear protein import within the atherosclerotic vessel.
In summary, our work has demonstrated the feasibility of studying the molecular mechanisms of infection-induced atherosclerosis using an ex vivo coronary culture system. Importantly, our data has provided the first direct evidence that an active C. pneumoniae infection alone, without contributions from a host immune system, can mediate endothelial dysfunction and stimulate arterial thickening, two key remodelling processes present during atherosclerotic progression. Our findings further suggest the involvement of Hsp60 as a key contributor in growth-based pathologies like C. pneumoniae-mediated atherosclerosis possibility through modulation of nuclear protein import.
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