A conformational change in C-reactive protein produces novel pro-inflammatory and thrombotic changes following myocardial infarction

C-reactive protein (CRP) has long been associated with cardiovascular disease. Following the recognition that progressive atherosclerosis and thrombosis was a dynamic process driven by chronic vascular inflammation highly sensitive CRP assays revealed that even mild elevations of CRP were associated with increased cardiac morbidity and mortality. This finding has generated tremendous interest in whether CRP is either a marker or mediator of cardiovascular disease, potentially providing a novel therapeutic target. There is currently conflicting evidence in the literature ensuring no definitive answer to this important question. It was previously recognised that CRP could undergo dissociation to individual monomers. However, it was not until recently that a biologically plausible mechanism by which the normally stable CRP pentamer could undergo this structural transformation was identified. This thesis explores the mechanism by which monomeric CRP can undergo this process, how this is regulated and controlled in vivo and the biological activity of monomeric CRP with a particular focus on myocardial infarction and platelet activation. In a series of experiments these concepts are developed and explored using in vitro, in vivo and human models. This serves to identify CRP as a therapeutic target for the treatment of myocardial infarction and other inflammatory disorders. This includes the first described method to inhibit CRP dissociation as a novel treatment approach with tremendous clinical potential, work which is to be continued with further refined compounds and anti-CRP agents