MCAM/CD146 Which is Differentially Expressed in Vascular Diseases, is a Potential Biomarker in Abdominal Aortic Aneurysm

Abstract

Introduction - AAA is characterized by chronic inflammation, apoptosis of vascular smooth muscle cells (VSMC), angiogenesis, extracellular matrix degradation, microcalcification and oxidative stress, processes that lead to the aorta degeneration. The role of VSMCs during the development and progression of AAA is not yet defined but their apoptosis results in the loss of the cells primarily responsible for the synthesis of extracellular matrix proteins. Cell adhesion molecules have been reported to be involved in the progression of atherosclerosis and plaque vulnerability. CD146 is an adhesion molecule located essentially in the vascular system and also present as a soluble form (sCD146) in the bloodstream. Although CD146/sCD146 has been previously associated with cardiovascular diseases, its potential role in AAA has not been addressed. Because of its role in angiogenesis, lymphocyte activation, tissue regeneration, inflammatory response and cellular senescence regulation, processes modulated in AAA, we hypothesized that CD146/sCD146 could play a role in AAA pathogenesis. Therefore, we investigated CD146 expression in AAA and its potential as a biomarker for AAA. Methods - We analyzed aortic samples from patients undergoing AAA repair in comparison with those from healthy multiorgan donors and femoral samples from atherosclerotic disease (AD) patients. Vascular tissue samples were studied using real-time PCR, immunohistochemistry and Western Blot. CD146, VSMC cell marker and endothelial cell marker genes transcript levels were determined relative to b-actin. Plasma levels of sCD146 were quantified by ELISA. Results - CD146 mRNA transcript levels were significantly lower in AAA (n=89) than in control aortas (n=17; p<0.001) and AD patients (n=15; p<0.001). Plasma levels of sCD146 were lower in AAA than in control and AD (AAA, 273.87±14.20, controls, 385.75±13.57; AD, 323.18±11.73 pg/ml; mean ± SEM) being differences statistically significants. When AAA patients were stratified according to maximum aortic diameter in: £55 mm, 55–69.9 mm and ≥70 mm, the expression of CD146 mRNA and sCD146 was already decreseased in the £55 mm group. Immunohistochemistry showed that CD146 was expressed mainly in the medial layer and endothelial cells from the microvasculature of the tissues. VSMC mRNA cell markers display the same expression profile than CD146 mRNA, in contrast to endothelial cell markers, wich were higher in AAA and AD than in controls. A positive correlation between CD146 mRNA and both cell markers was found in AAA but not in controls. In the experimental AngII induced AAA mouse model CD146 aortic mRNA levels were also decreased in AAA mice compared with control mice. Conclusion - We showed that CD146/sCD146 expression was significantly lower in AAA patients when compared with healthy individuals and, more importantly, with patients having atherosclerotic pathology without AAA and that mRNA levels correlates with VSMC markers genes in AAA. As VSMC apoptosis is revealed by downregulation of VSMC marker genes, CD146 could be a marker of VSMC loss, but this fact still remains uncertain. As CD146 is differently expressed in AD and AAA, CD146 could be a putative new marker for AAA. Further investigations will be needed to evaluate the role of CD146 in AAA pathology.