Abstract
Coronary atherosclerosis still represents the major cause of mortality in western societies. Initiation of atherosclerosis occurs within the intima, where major histological and molecular changes are produced during pathogenesis. So far, proteomic analysis of the atherome plaque has been mainly tackled by the analysis of the entire tissue, which may be a challenging approach because of the great complexity of this sample in terms of layers and cell type composition. Based on this, we aimed to study the intimal proteome from the human atherosclerotic coronary artery. For this purpose, we analyzed the intimal layer from human atherosclerotic coronaries, which were isolated by laser microdissection, and compared with those from preatherosclerotic coronary and radial arteries, using a two-dimensional Differential-In-Gel-Electrophoresis (DIGE) approach. Results have pointed out 13 proteins to be altered (seven up-regulated and six down-regulated), which are implicated in the migrative capacity of vascular smooth muscle cells, extracellular matrix composition, coagulation, apoptosis, heat shock response, and intraplaque hemorrhage deposition. Among these, three proteins (annexin 4, myosin regulatory light 2, smooth muscle isoform, and ferritin light chain) constitute novel atherosclerotic coronary intima proteins, because they were not previously identified at this human coronary layer. For this reason, these novel proteins were validated by immunohistochemistry, together with hemoglobin and vimentin, in an independent cohort of arteries.
Highlights
Coronary heart disease remains the major cause of mortality in developed countries
Intimal thickening produced by the migration of vascular smooth muscle cells (VSMCs)1 to the subendothelium, where they synthesize extracellular matrix (ECM), appears during normal development and aging [3], in response to minimal endothelium injury often produced by a disturbance in the pattern of blood flow at bending points and near bifurcations of the arterial tree [4]
Comparative proteomic analysis of any arterial layer during atherogenesis has only been performed once, by focusing on carotid intima layer proteoglycans compared with mammary intimal ones, using a semi-quantitative approach based on peptide intensities from MS analysis [16]
Summary
Coronary heart disease remains the major cause of mortality in developed countries. In particular, coronary atherosclerosis is the responsible for the majority of the acute coronary syndromes. Intimal thickening produced by the migration of vascular smooth muscle cells (VSMCs) to the subendothelium, where they synthesize extracellular matrix (ECM), appears during normal development and aging [3], in response to minimal endothelium injury often produced by a disturbance in the pattern of blood flow at bending points and near bifurcations of the arterial tree [4]. Atherosclerosis initiates at this locations with circulating leukocytes recruitment because of vascular endothelium alteration, which triggers the expression of adhesion molecules (VCAM) [3]. The abbreviations used are: VSMC, vascular smooth muscle cell; 2-DE, two-dimensional electrophoresis; ACB, atherosclerotic coronary biopsy; ANXA4, annexin A4; CAN, atherosclerotic coronary necropsy; EC, endothelial cell; ECM, extracellular matrix; FLC, ferritin light chain; H&E, hemtoxilin/eosin staining; IHC, immunohistochemistry; LMD, laser microdissection; LMPC, laser microdissection and pressure catapulting; MFAP4, microfibril-associated glycoprotein 4; MRLC, myosin regulatory light 2, smooth muscle isoform; OGN, osteoglycin; PCN, preatherosclerotic coronary necropsy; PRB, preatherosclerotic radial biopsy; SaP, serum amyloid protein
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