PTX3 is a biomarker of cardiovascular diseases and exerts protective functions in acute myocardial infarction and atherosclerosis. Here we aimed at investigating the role of PTX3 in cardiovascular diseases. First we studied the role of PTX3 in arterial thrombosis induced by FeCl3 injury: PTX3 KO mice showed a 60% reduction in carotid artery blood flow with a greater thrombus formation compared to 20% of WT mice (p<0.01) following arterial thrombosis, an effect mediated by PTX3 derived from non-hematopoietic cells: indeed, PTX3 KO mice transplanted with bone marrow from WT or PTX3 KO mice presented a significant increased carotid occlusion compared to WT mice transplanted with bone marrow from WT or PTX3 KO mice (p<0.01). This effect was independent of altered hemostatic properties, impaired platelet activation, modulation of P-selectin activity as P-selectin KO/PTX3 KO mice showed a significant reduction in carotid artery blood flow and increased arterial thrombus formation compared to P-selectin KO (p<0.01). PTX3 was shown to localize between the damaged artery and thrombus and to reduced platelet aggregation induced by collagen and fibrinogen (p>0,01), an effect related mainly to the C-terminal and N-terminal domain respectively. Finally, exogenous administration of hrPTX3 reverted the pro-thrombotic phenotype in PTX3 KO mice and improves the outcomes in WT (p<0.01). In conclusion, PTX3 deficiency is associated with increased arterial thrombosis via modulation of collagen and fibrinogen thrombogenicity. In parallel, we investigated the role of PTX3 in the immune-inflammatory response associated to obesity and metabolic disorders, a condition deeply associated with the incidence of cardiovascular events. After 20 weeks of high fat diet (HFD,45% of calories from fat), PTX3 KO mice compared to WT, showed a decreased weight gain (p<0.05), coupled to a decreased accumulation of fat at both 10 and 20 weeks in the visceral (VAT,p<0.05) and subcutaneous adipose depots (SCAT,p<0.05) measured by magnetic resonance for imaging. Basal glycaemia at both 10 and 20 weeks was similar between groups as well as glucose and insulin tolerance measured by glucose (GTT) and insulin tolerance test (ITT), excluding a direct role of PTX3 on glucose homeostasis. As PTX3 is a key component of innate immunity, we focused our attention on the inflammatory response in VAT of PTX3 KO: adipocyte size was significantly smaller (p<0.01) and associated with a decreased infiltration of leukocytes and expression of pro-inflammatory cytokines (MCP-1, IL-6, p<0.05) compared to WT. These data show that deficiency of PTX3 results in reduced HDF-induced obesity as a consequence of a decreased inflammatory state of PTX3 KO VAT. Concluding, we have shown the dual role of PTX3 which plays a protective role in arterial thrombosis, while in a model of diet-induced obesity is associated with the promotion of inflammation and fat deposition in adipose tissue. This dual role suggests that PTX3 may play different functions depending on the origin and the site of action.
ROLE OF THE LONG PENTRAXIN 3 (PTX3) IN CARDIOMETABOLIC DISEASES / F. Bonacina ; supervisor: G. Norata ; coordinator: A. Corsini, A. Catapano, A. Panerai. - Milano : Università degli studi di Milano. DIPARTIMENTO DI SCIENZE FARMACOLOGICHE E BIOMOLECOLARI, 2016 Jan 12. ((28. ciclo, Anno Accademico 2015.
|Titolo:||ROLE OF THE LONG PENTRAXIN 3 (PTX3) IN CARDIOMETABOLIC DISEASES|
|Supervisori e coordinatori interni:||PANERAI, ALBERTO EMILIO|
CATAPANO, ALBERICO LUIGI
NORATA, GIUSEPPE DANILO
|Data di pubblicazione:||12-gen-2016|
|Parole Chiave:||PTX3; arterial thrombosis; obesity and metabolic disfunctions; visceral adipose tissue|
|Settore Scientifico Disciplinare:||Settore BIO/14 - Farmacologia|
|Citazione:||ROLE OF THE LONG PENTRAXIN 3 (PTX3) IN CARDIOMETABOLIC DISEASES / F. Bonacina ; supervisor: G. Norata ; coordinator: A. Corsini, A. Catapano, A. Panerai. - Milano : Università degli studi di Milano. DIPARTIMENTO DI SCIENZE FARMACOLOGICHE E BIOMOLECOLARI, 2016 Jan 12. ((28. ciclo, Anno Accademico 2015.|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.13130/f-bonacina_phd2016-01-12|
|Appare nelle tipologie:||Tesi di dottorato|