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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.

Identifying the molecular and genetic pathways important for heart development and deciphering the causes of CHD are still a challenging puzzle. A newly identified piece of this puzzle is KLF13, a member of the Krüppel-like family of zinc-finger proteins, was found to be important for atrial septation and ventricular trabeculation of Xenopus embryos. The protein is expressed predominantly in the heart, binds evolutionarily-conserved regulatory elements on cardiac promoters, and activates cardiac transcription. In this study we examined KLF13 mechanism of action by investigating its transcriptional activity on the ANF promoter using a deletion/mutagenesis approach. We reported the identification of a new synergistic partnership between KLF13 and the individual cardiac transcription factors TBX5, NKX2.5, PEX1, and CATF1. Also, we localized KLF13’s transcriptional activation domain, the nuclear localization region/zinc-fingers, and the DNA binding zinc-fingers. This study will provide insight into the contribution of KLF13 to the development of CHDs.

High mortality rates from cardiovascular disease underscore the need for improved therapies. Thus, it is important to further our understanding of factors and mechanisms promoting cardiac protection and repair. Fibroblast growth factor-2 (FGF-2), administered to the heart before or during injury exerts beneficial effects such as cytoprotection and angiogenesis. However, the effects of a chronic elevation in endogenous FGF-2 on recovery/remodeling after ischemic injury are not known. My hypothesis was that chronic elevation in endogenous FGF-2 expression (in FGF-2 overexpressing transgenic mice) exerts beneficial effects such as improved function after isoproterenol-induced injury in vivo. The first study showed that treatment with the β-adrenergic agonist isoproterenol resulted in exaggerated levels of cellular infiltration and myocardial disarray in transgenic FGF-2 versus non-transgenic mouse myocardium. This was suggestive of increased cardiac injury in transgenic FGF-2 mice. Inhibition of T cells using the immunosuppressants cyclosporine A or antibodies against CD3ε attenuated cellular infiltration in transgenic FGF-2 mice, to levels comparable to those of non-transgenic mice, suggesting a T lymphocyte-mediated effect. Overall morphological data suggested that chronic FGF-2 elevation might have created an adverse outcome after cardiac injury. In a follow-up study the effect of chronic FGF-2 elevation on cardiac function was examined, as measured by tissue Doppler imaging (TDI), after isoproterenol administration. FGF-2 overexpressing mice displayed improved cardiac function compared to controls, after isoproterenol, both acutely (24 h) and in a sustained fashion (2-4 weeks). The FGF-2 associated functional improvement at 2-4 weeks was attenuated following immunosuppression with cyclosporine A, but not treatment with anti-CD3ε antibodies. The FGF-2–associated functional improvement may be partially attributed to a cyclosporine A-sensitive (but anti-CD3-insensitive) infiltrating cell population. Thus cellular infiltration, in response to elevated FGF-2, may have a net beneficial effect. In a third study, non-transgenic mice were put through a brief swimming protocol (exercise) prior to isoproterenol. This acute bout of exercise resulted in significant improvement in TDI function, compared to control groups, measured at 24 hours up to 4 weeks post-isoproterenol. In conclusion, increased endogenous cardiac FGF-2 expression, or an acute bout of exercise, exert sustained beneficial effects against isoproterenol-induced cardiac injury.

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