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.

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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Adenosine is a nucleoside with varied pharmacological effects but its actions in man are sparsely documented. Cardiac and respiratory effects of adenosine in man were examined. Adenosine was found to increase coronary flow in patients without significant coronary atheroma. Adenosine restored sinus rhythm in some patients with supraventricular tachycardia. In those in whom sinus rhythm was not restored the underlying rhythm was atrial flutter. In patients with complete heart block adenosine decreased ventricular rate in a dose-related fashion. In subjects in sinus rhythm adenosine produced a transient dose-related bradycardia which was followed by a more sustained increase in sinus rate. These latter effects were compared but were found not to differ in young and elderly subjects. A dose-related respiratory stimulant effect of adenosine, which had not previously been widely appreciated, was observed. The possible relevance of this observation to the ventilatory response to hypoxia is discussed. Adenosine-induced respiratory stimulation was found not to differ in young and elderly subjects. Dipyridamole, an inhibitor of adenosine transport, potentiated adenosine-induced respiratory stimulation and bradycardia but not the subsequent tachycardia. Aminophylline, a competitive adenosine antagonist at cell-surface receptors, abolished adenosine-induced bradycardia but did not alter the tachycardia or respiratory stimulation. Adenosine-induced bradycardia in man may be explained by an action of adenosine on cell-surface receptors at one site, whereas such an explanation does not accord with the observations on tachycardia and respiratory stimulation. Adenosine administered proximal to the carotid circulation in man stimulated respiration, but infusion distal to those vessels had no such effect. These observations are consistent with the hypothesis that adenosine stimulates respiration in man by an action on the carotid body. Possible physiological, pathophysiological and therapeutic implications of these observations are discussed.

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