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Chemokine axes and inflammatory status in Metabolic Syndrome. Effect of PCSK9 inhibitors in the systemic inflammation associated to Familial Hypercholesterolemia

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Chemokine axes and inflammatory status in Metabolic Syndrome. Effect of PCSK9 inhibitors in the systemic inflammation associated to Familial Hypercholesterolemia

dc.contributor.advisor	Sanz Ferrando, María Jesús
dc.contributor.advisor	Piqueras Ruiz, Laura
dc.contributor.author	Gomes Marques, Patrice
dc.contributor.other	Departament de Farmacologia	es_ES
dc.date.accessioned	2020-02-03T12:12:32Z
dc.date.available	2020-02-04T05:45:05Z
dc.date.issued	2019	es_ES
dc.date.submitted	07-02-2020	es_ES
dc.identifier.uri	https://hdl.handle.net/10550/72833
dc.description.abstract	Metabolic syndrome (MS) is a metabolic disorder characterized by a cluster of cardiovascular risk factors and its prevalence remains increasing in Western world. It is associated to low-grade systemic inflammation, a key driver of premature atherosclerosis and the major cause of cardiovascular disease (CVD). Given that CXCL16/CXCR6, CX3CL1/CX3CR1 and CCL2/CCR2 axes have been implicated in the development of CVD, we investigated the role of these axes in leukocyte adhesion to the dysfunctional arterial endothelium in a MS model. We also performed a comprehensive analysis of different cellular and soluble immune players in patients with MS. When compared with the controls, MS patients presented a CXCR6 and CX3CR1 up-regulation in platelets and several leukocytes subsets. In both groups, leukocyte adhesion to the arterial endothelium was significantly increased after TNFalpha stimulation; however, this effect was significantly higher in MS subjects than in control subjects. Notably, leukocyte adhesion was significantly reduced by the neutralization of endothelial CXCL16, CX3CL1 or CCL2 in MS patients but not in the control group. Therefore, CXCR6 or CX3CR1 expression on immune players may constitute a new membrane-associated biomarker for adverse cardiovascular events in MS. Moreover, pharmacological modulation of CXCL16/CXCR6, CX3CL1/CX3CR1 or CCL2/CCR2 chemokine axes may positively affect cardiovascular outcome in MS. Familial hypercholesterolemia (FH) is characterized by elevated plasma levels of LDL cholesterol, a result of enhanced LDL receptor (LDL-R) degradation and/or impairment of LDL-R/LDL binding. Given that proprotein convertase subtilisin/kexin type 9 (PCSK9) is involved in LDL-R degradation, during the last years, some monoclonal antibodies against human PCSK9 have been developed and demonstrated efficacy in lowering LDL plasma levels. In this study, we investigated the effect of PCSK9 silencing on endothelial dysfunction induced by TNFalpha and the impact of PCSK9 inhibitors in the systemic inflammation associated to FH. Therefore, a monoclonal antibody against PCSK9 (alirocumab) was administered for eight weeks to FH patients and different parameters were determined before and after the treatment. TNFalpha stimulation of arterial endothelial cells caused up-regulation of PCSK9. The in vitro approaches suggest that PCSK9 inhibition reduces the expression of cell adhesion molecules and membrane-bound chemokines, as well as the generation and release of soluble chemokines. Alirocumab reduced platelet and leukocyte activation, as well as CX3CR1, CXCR6 and CCR2 expression on several leukocyte subsets and decreased leukocyte adhesion in FH patients. Therefore, PCSK9 blockade might reduce endothelial dysfunction and constitute a new promising therapeutic approach in the control of FH inflammatory state, preventing further cardiovascular events in this cardiometabolic disease.	es_ES
dc.format.extent	298 p.	es_ES
dc.language.iso	en	es_ES
dc.subject	metabolic disorders	es_ES
dc.subject	immunopharmacology	es_ES
dc.subject	chemokines	es_ES
dc.subject	leukocyte-endothelium interactions	es_ES
dc.subject	vascular inflammation	es_ES
dc.subject	atherosclerosis	es_ES
dc.subject	metabolic syndrome	es_ES
dc.subject	familial hypercholesterolemia	es_ES
dc.title	Chemokine axes and inflammatory status in Metabolic Syndrome. Effect of PCSK9 inhibitors in the systemic inflammation associated to Familial Hypercholesterolemia	es_ES
dc.type	doctoral thesis	es_ES
dc.subject.unesco	UNESCO::CIENCIAS MÉDICAS ::Farmacología	es_ES
dc.embargo.terms	0 days	es_ES