Identificación de nuevos biomarcadores de aneurisma aórtico abdominal y de aterosclerosis subclínica mediante herramientas proteómicas de última generación

Zusammenfassung

Cardiovascular diseases (CVD) one of the main causes of mortality in the world. Clinical complications are associated with rupture of the arterial wall, of the intimal layer in the case of atherosclerosis and of the adventitial layer, in abdominal aortic aneurysm (AAA). Both pathologies are asymptomatic and the mechanisms underlying their presence and development are not fully understood. In addition, current therapies based on the control of risk factors are of limited value, because subjects without risk factors are also able to develop CV events. Therefore, this thesis has the purpose to identify novel pathophysiological mechanisms underlying the development of these pathologies, as well as new diagnostic, prognostic or therapeutic biomarkers by using different state-of-the-art proteomic techniques. Low high-density lipoprotein cholesterol levels (HDLc) are related with the presence and evolution of CVD. However, the pharmacological modulation of HDLc levels has not been effective in the prevention of CVD. It has been postulated that the constituent or associated protein cargo of these particles are responsible for providing their vasculoprotective functions, and in turn, alterations of the proteins of these particles could affect its functionality. Therefore, we have been able to identify how the HDL of aneurysmal patients are characterized by an increase in proteins related to redox homeostasis, as well as by an increase in posttranslational modifications (PTMs), mainly oxidative modifications, on the main constitutive protein of these particles, namely apolipoprotein A1 (APOA1). On the other hand, we have also been observed how the efflux of cholesterol, the principal cardioprotective function of these particles, is diminished in AAA patients. In conclusion, our data indicate that HDLs are dysfunctional in patients with AAA, and this may be due to the alteration in HDLs protein cargo or in the presence of oxidative modifications. The study of the pathogenesis atherosclerosis has been mainly focused on the final stages of this pathology; however, its development begins earlier. Therefore, in this work we wanted to analyse at the tissue level the composition of the media and intima layer of aortas with subclinical atherosclerosis, to search for the processes that may be involved in the development of atherogenesis. We have been able to determine how these initial stages are characterized by a deposit of very abundant plasmatic proteins, in which the complement system plays a prominent role, specially the components of the lytic pathway, which cause activation of the membrane attack complex (MAC) associated with a decrease in negative regulators. In addition, one of its main components, the complement C5 has been identified as a new biomarker of atherosclerotic in patients with subclinical atherosclerosis. In summary, this work has been able to present a broad characterization of the protein composition on the incipient atherosclerotic plaques and the mechanisms involved in the development of this pathology.