Responsabilie di unità operativa nel progetto “Identification of proteomic/proinflammatory and immune biomarkers in patients with Acute Coronary Syndromes at high risk to develop clinical events: genomic and proteomic approaches” Ministero della Salute, Ricerca Finalizzata 2007 – Progetto Strategico

Acute coronary syndromes (ACS) represent a major health concern in modern medicine. Despite the advances in our knowledge of its pathophysiology, diagnosis, and therapy, major improvements are still needed, particularly among subgroups of patients at relatively high risk. Several studies indicate that elevated levels of systemic markers of inflammation are associated with a worst prognosis, due to recurrent episodes of coronary instability. Although the measurement of systemic markers of inflammation is useful for prognostic stratification, they do not represent potential therapeutic targets. In contrast, recent data indicate that the identification of dis-regulated immune pathways might open the avenue to novel therapeutic approaches, as well as to a better prognostic stratification of ACS. The increased levels of growth factors and inflammatory cytokines/ chemokines observed in ACS patients may also induce endothelial progenitor cell (EPC) mobilization and function. Recently, microRNAs (miRNAs) have emerged as important regulators of gene expression in mammals. MiRNAs are small noncoding molecules that regulate the stability or the translational efficiency of target messenger RNAs. Although miRNA has been implicated in the pathogenesis of several processes including tumorigenesis, their role in ACS-associated EPC dysfunction is unknown. Increasing evidence indicates that individuals with chronic renal insufficiency are more likely to die of cardiovascular disease than to develop kidney failure, and that renal insufficiency represents the most important independent predictor of adverse prognosis in most cardiovascular events, including acute coronary syndromes (ACS). The mechanisms linking renal insufficiency to increased mortality risk in patients with ACS have not been completely defined. Renal insufficiency (RI) associated to coronary artery disease often causes modifications in platelet function and reactivity, influencing signal transduction pathways, which ultimately lead to the thrombotic complications associated with the disease. RI patients have a high prevalence of cardiovascular and thrombotic complications. The results of the study will provide mechanistic/molecular data on the relations between RI and the negative prognosis of ACS patients during the acute phase of the disease. Thus, the study will provide: ·Identification of molecular markers responsible for haemostatic/thrombotic complications of ACS patients with RI through a biochemical and molecular (genomic and proteomic) approach, also using high throughput techniques (genomic and proteomic). ·Validation of the prognostic value of the abundance and function of circulating EPC in ACS, also in relation to RI. Data will be provided on miRNAs expressed in ACS-derived EPC, also in relation to the inactivation of their regenerative potential. ·Assessment of the role of effector T-cells with a functional profile predisposing to vascular injury. We will also test the hypothesis that the immune response observed in ACS might depend on a tolerance break due to defective regulation of the Tlymphocyte compartment, providing a potential explanation for difference between stable and acute manifestations of atherosclerosis, in relation to RI, in spite of common plaque structure and antigenic content.