A proteomic approach to the study of human thoracic aorta aneurysms

Cardiovascular disease is the leading cause of illness and death in the whole world. In the United States, for example, there are an estimated 62 million people with cardiovascular disease. In 2000, approximately 946,000 deaths were attributed to cardiovascular disease, accounting for 39% of all deaths in the USA. Among these causes of death thoracic aorta aneurysms (TAAs) can be found. Both familial and nonfamilial nonsyndromic thoracic aortic aneurysms (NSTAAs) are less well characterized than syndromic ones. This is the aim of my thesis: increasing our knowledge about the specific morphological and molecular characteristics that underlie NSTAAs. Tunica media samples taken from nine selected nonfamilial NSTAAs and nine reference patients were investigated via proteomics-bioinformatics, immunoblotting, quantitative histology (QH), and immunohistochemistry (IHC)/immunofluorescence (IF). The first characteristic I observed is a deep disorganization at extracellular matrix (ECM) level. I found a distorted elastic fiber network partnered with an increase in collagen fibers. The vascular smooth cells (VSMCs) decreased in number due to a proapoptotic increase in Caspase-3 activity. In the same media samples cystathionine gamma-lyase (CTH) was diffusely upregulated, and by producing H2S might be responsible for both the apoptosis and a hindered cell proliferation. VSMCs presented even a change in their phenotype, switching from a contractile to synthetic/secretory one. At the ECM level I found an increase in Paxillin (PXN) holoprotein, and in its cleaved form. Expression of the Testican-2 proteoglycan was also boosted. Conversely, the microfibrillar-associated glycoprotein-1 (MAGP-1) was found decreased. Alterations at the cytoskeletal level were also present; in fact there was a significant down-regulation in Vimentin (VIM) expression. Moreover, I found deeply altered even two important cell signaling systems in NSTAAs. On the one hand, an upregulation of Jagged1 (JAG1) holoprotein and its receptor, Notch1, whose signal was hindered by an accumulation of extracellular soluble JAG1 fragments. On the other hand, I observed an upregulated ectodysplasin (EDA) protein combined with a downregulation of its receptor (EDAR). In conclusion, I found a weakening of the aortic wall caused by an imbalance between elastic and fibrosis components in NSTAAs. This imbalance is coupled with a perturbed ratio between dying and proliferating cell fractions. In NSTAAs I found even deep alterations in ECM, cytoskeleton, and cell signaling. All together these changes concur to aneurysm progression.