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The vascular extracellular matrix (ECM) is essential for the structural integrity of the vessel wall and also serves as a substrate for the binding and retention of secreted products of vascular cells as well as molecules coming from the circulation. Although proteomics has been previously applied to vascular tissues, few studies have specifically targeted the vascular ECM and its associated proteins. Thus, its detailed composition remains to be characterized. In this study, we describe a methodology for the extraction of extracellular proteins from human aortas and their identification by proteomics. The approach is based on (a) effective decellularization to enrich for scarce extracellular proteins, (b) successful solubilization and deglycosylation of ECM proteins, and (c) relative estimation of protein abundance using spectral counting. Our three-step extraction approach resulted in the identification of 103 extracellular proteins of which one-third have never been reported in the proteomics literature of vascular tissues. In particular, three glycoproteins (podocan, sclerostin, and agrin) were identified for the first time in human aortas at the protein level. We also identified extracellular adipocyte enhancer-binding protein 1, the cartilage glycoprotein asporin, and a previously hypothetical protein, retinal pigment epithelium (RPE) spondin. Moreover, our methodology allowed us to screen for proteolysis in the aortic samples based on the identification of proteolytic enzymes and their corresponding degradation products. For instance, we were able to detect matrix metalloproteinase-9 by mass spectrometry and relate its presence to degradation of fibronectin in a clinical specimen. We expect this proteomics methodology to further our understanding of the composition of the vascular extracellular environment, shed light on ECM remodeling and degradation, and provide insights into important pathological processes, such as plaque rupture, aneurysm formation, and restenosis.
Abdominal aortic aneurysms (AAA) are characterized by pathological remodeling of the aortic extracellular matrix (ECM). However, besides the well-characterized elastolysis and collagenolysis little is known about changes in other ECM proteins. Previous proteomics studies on AAA focused on cellular changes without emphasis on the ECM. In the present study, ECM proteins and their degradation products were selectively extracted from aneurysmal and control aortas using a solubility-based subfractionation methodology and analyzed by gel-liquid chromatography-tandem MS and label-free quantitation. The proteomics analysis revealed novel changes in the ECM of AAA, including increased expression as well as degradation of collagen XII, thrombospondin 2, aortic carboxypeptidase-like protein, periostin, fibronectin and tenascin. Proteomics also confirmed the accumulation of macrophage metalloelastase (MMP-12). Incubation of control aortic tissue with recombinant MMP-12 resulted in the extensive fragmentation of these glycoproteins, most of which are novel substrates of MMP-12. In conclusion, our proteomics methodology allowed the first detailed analysis of the ECM in AAA and identified markers of pathological ECM remodeling related to MMP-12 activity.
This registry analysis demonstrates the feasibility and potential procedure difficulties when using TAVI for severe NAVR. Acceptable results may be achieved in carefully selected patients who are deemed too high risk for conventional surgery, but the possibility of requiring 2 valves and leaving residual aortic regurgitation remain important considerations.
The present study characterized the metabolic adaptation to persistent AF, unraveling a potential role for ketone bodies, and demonstrated that discordant metabolic alterations are evident in individuals susceptible to post-operative AF.
Objective-To investigate the hypothesis that release of adipokines by epicardial adipose tissue (EAT) is dysregulated in obesity and/or coronary artery disease (CAD), along with the previously documented expansion of the tissue, and that these molecules induce pathophysiological changes in human monocytes and coronary artery endothelial cells. Methods and Results-In white nondiabetic patients with CAD (nϭ62) or without CAD (control group) (nϭ32), subdivided by body mass index of Յ27 and Ͼ27, 13 cytokines were identified by protein array analysis as EAT products. Interleukin 6, interleukin 8, monocyte chemoattractant protein 1, plasminogen activator inhibitor 1, growth-related oncogene-␣, and macrophage migration inhibitory factor were the most abundant. Adiponectin release was suppressed in patients with obesity and CAD, and regulated on activation T-cell and secreted (RANTES) was induced in patients with CAD. EAT-conditioned media induced migration of monocytic tryptophan hydroxylase 1 (THP-1) cells, an effect exacerbated in those with CAD. Moreover, conditioned media from patients with CAD and body mass index of Ͼ27 increased the adhesion of THP-1 cells to human coronary artery endothelial cells by 15.1% (Pϭ0.002) and expression of intercellular adhesion molecule 1 by 2.8-fold (Pϭ0.002). This effect was reversed by recombinant adiponectin.
Conclusion-EAT
If patients are stratified well, excellent survival can be achieved in the treatment of pulmonary atresia with intact ventricular septum. This result may be at the price of achieving a 1-ventricle as opposed to a 2-ventricle repair.
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