Peripheral Artery Disease: The search for a biological marker

• Autores: Anna Hernández Aguilera
• Directores de la Tesis: Vicente Martín Paredero (dir. tes.), Jorge Joven Maried (dir. tes.)
• Lectura: En la Universitat Rovira i Virgili ( España ) en 2017
• Idioma: español
• Tribunal Calificador de la Tesis: Juan Rubiés Prat (presid.), Ramón Deulofeu Piquet (secret.), Manuel Castro Cabezas (voc.)
• Programa de doctorado: Programa de Doctorado en Biomedicina por la Universidad Rovira i Virgili
• Materias:
  • Química
    • Bioquímica
  • Ciencias de la vida
    • Fisiología humana
      • Metabolismo humano
• Enlaces
  • Tesis en acceso abierto en:  hdl.handle.net  TDX 
• Resumen

  • Peripheral artery disease (PAD) is a common manifestation of systemic atherosclerosis affecting peripheral arteries. Despite affecting more than 200 million patients in industrialized countries, PAD is often underdiagnosed. The first stages of the disease are asymptomatic and thus, to perform an early diagnose becomes difficult. Patients can undergo different treatment according disease severity: management of cardiovascular risk factors, exercise, rehabilitation and pharmacological intervention. In advanced stages, vascular specialists usually perform invasive surgical procedures.

    The ankle-brachial index (ABI) is the most used test for PAD diagnosis although it presents some limitations. It is an easy technique based on the ratio between the pressure of ankle arteries and the pressure of brachial artery of the arm. There are additional circulating biomarkers of diagnosis, mainly based on cardiovascular risk factors, inflammation or oxidative process; they are not exclusively for PAD but for atherosclerosis in general.

    Inflammation, oxidation, vascular remodeling and mitochondrial dysfunction play an important role in the development of atherosclerosis. We hypothesized that an increased knowledge on these processes would provide circulating biomarkers for the disease as well as possible therapeutic strategies.

    In Study 1 (International Journal of Molecular Sciences), we performed a tissue characterization by investigating the immunohistochemical expression of paraoxonases (PON) and chemokines in arteries of PAD patients. Results showed that PON1 and PON3 were increased in atherosclerotic arteries, probably by PPARγ- and NFκβ-mediated pathways, suggesting an oxidative stress prevention and foam cell formation during atherosclerosis. Chemokine (C-C motif) ligand 2 (CCL2) and atypical chemokine receptors (ACKR) DARC and D6 were also significantly increased in affected arteries, although they did not show a uniform distribution among artery layers. This increased expression of CCL2 may be related to the inflammatory conditions within the artery wall. The expression of ACKRs, which bind to CCL2 but do not exert signal transmission, may modify chemokine availability and cell migration.

    Extracellular matrix (ECM) turnover is also involved in vascular remodeling. In Study 2 (Journal of Vascular Surgery), by combining histological and proteomics approaches, we confirmed a significant artery remodeling in of PAD patients. Atherosclerotic arteries showed a specific protein profile in which ECM-related components were underexpressed, suggesting a possible degradation of the ECM. We then measured a panel of ECM fragments of degradation (neo-epitopes) by ELISA in serum samples of PAD patients. Neo-epitopes of versican degradation (VCANM) and type IV collagen degradation fragments (C4M) showed potential as biomarkers to segregate patients across the spectrum of PAD.

    Impaired metabolism and mitochondrial dysfunction may also predispose to disease. In Study 3 (Translational Research), we used a targeted metabolomics methodology to assess the plasma metabolome of PAD patients. Many of measured metabolites were connected not with PAD, but with associated comorbidities (hypertension, type-2 diabetes, dyslipidemia), age or body mass index. We discarded these metabolites as PAD biomarkers, and focused on the 6 remaining metabolites directly related to PAD. (Iso)citrate and glutamate showed the best discriminant capacity not only between control volunteers and PAD patients, but also for an early detection of the disease.