Abstract 136: Identification of Melanoregulin as Novel Marker for Atherosclerosis
Introduction: Novel biomarkers identification in atherosclerosis is needed for early detection/intervention of vascular diseases. Impaired lysosomal function and autophagy cause abnormal lipid accumulation in foam cells and contribute to atherosclerosis progression. By microarray of human carotid plaques in the Biobank of Karolinska Endarterectomies (BiKE), we found that melanoregulin (MREG), a protein associated with lysosomes, phagocytosis and autophagy and previously not associated with atherosclerosis, was significantly up-regulated in symptomatic (S) versus asymptomatic (AS) patients. MREG expression was also significantly correlated to inflammatory, lipid and endo/lysosome markers.
Hypothesis: We hypothesized that MREG modulates clearance of engulfed lipids and extracellular material in lipid-loaded foam cells.
Methods: MREG mRNA and protein levels were evaluated in human carotid plaque tissue from S and AS patients by qPCR and immunohistochemistry, respectively. MREG, together with lysosome and lipid markers (LAMP2 and PLIN2 respectively) was identified by immunofluorescence in human monocyte cells (THP-1), loaded with modified LDL. To investigate autophagy/MREG correlation, THP-1 cells were incubated with autophagy inhibitor (chloroquine, CQ) and MREG mRNA was assessed by qPCR.
Results: MREG mRNA is elevated in human atherosclerotic lesions versus normal artery (11.21 folds, P<0.0001). In human aortic tissue MREG expression is correlated to the lesion progression and localizes in infiltrating macrophage-derived foam cells. In the human carotid plaque, MREG co-localizes with CD68+ and PLIN2+ cells, lined to the necrotic core. MREG protein was also detected in PMA-differentiated THP-1 cells. In lipid-loaded THP-1, MREG is co-localized with lysosomal LAMP2. Moreover, MREG expression is increased in THP-1 cells by incubation with PMA, starving medium and CQ.
Conclusions: We show here for the first time that MREG is expressed in atherosclerotic lesions and is associated with endo/lysosomes in human macrophages. Furthermore we show that autophagy inhibition increases MREG mRNA expression. Future studies will investigate how MREG expression levels will affect phagocytic activity of lipid-loaded macrophages.
Author Disclosures: S. Aldi: None. L. Perisic: None. M. Lengquist: None. M. Kronqvist: None. J. Roy: None. A. Bäcklund: None. D.F.J. Ketelhuth: None. J.H. Lindeman: None. G.K. Hansson: None. G. Paulsson-Berne: None. U. Hedin: None.
- © 2015 by American Heart Association, Inc.