Expression of fatty acid–binding protein 4/aP2 is correlated with plaque instability in carotid atherosclerosis

• Published in: Journal of internal medicine Vol. 269; no. 2; pp. 200 - 210
• Main Authors: Agardh, H. E., Folkersen, L., Ekstrand, J., Marcus, D., Swedenborg, J., Hedin, U., Gabrielsen, A., Paulsson‐Berne, G.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-02-2011; Blackwell
• Subjects: Aged; Aged, 80 and over; Antigens, CD - metabolism; Antigens, Neoplasm - metabolism; atherosclerosis; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Biomarkers - metabolism; Blood and lymphatic vessels; Cardiology. Vascular system; Carotid Artery Diseases - metabolism; Carotid Artery Diseases - surgery; CD52 Antigen; Endarterectomy, Carotid; Fatty Acid-Binding Proteins - biosynthesis; Fatty Acid-Binding Proteins - genetics; Female; Gene Expression; Gene Expression Profiling - methods; General aspects; Glycoproteins - metabolism; Humans; inflammation; leucocytes; Macrophages - metabolism; Male; Medical sciences; Medicin och hälsovetenskap; Middle Aged; molecular medicine; Neurology; Plaque, Atherosclerotic - metabolism; Plaque, Atherosclerotic - surgery; Prospective Studies; RNA, Messenger - genetics; stroke; T-Lymphocyte Subsets - immunology; Vascular diseases and vascular malformations of the nervous system; Transcription factor AP2; Nervous system diseases; Stroke; Leukocyte; leucocytes; Lipids; Cardiovascular disease; Inflammation; Fatty acids; Artery; Cerebral disorder; Vascular disease; Medicine; Binding protein; Blood vessel; Carotid; Central nervous system disease; Atherosclerosis; molecular medicine; Instability; Circulatory system; Cerebrovascular disease
• ISSN: 0954-6820; 1365-2796; 1365-2796
• DOI: 10.1111/j.1365-2796.2010.02304.x

.  Agardh HE, Folkersen L, Ekstrand J, Marcus D, Swedenborg J, Hedin U, Gabrielsen A, Paulsson‐Berne G (Department of Medicine, Experimental Cardiovascular Research, Karolinska Institutet; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden). Expression of fatty acid–binding protein 4/aP2 is correlated with plaque instability in carotid atherosclerosis. J Intern Med 2011; 269: 200–210.
Objective.  The molecular basis for atherosclerotic plaque vulnerability with high risk of plaque rupture and thromboembolism is complex. We investigated whether clinical estimates of plaque stability correlate with differentially expressed mRNA transcripts within the lesion.
Methods and results.  Endarterectomy samples from patients undergoing surgery for symptomatic and asymptomatic carotid stenosis were prospectively collected and clinical parameters recorded in the Biobank of Karolinska Carotid Endarterectomies. mRNA expression profiling (n = 40) and quantitative RT‐PCR (n = 105) revealed increased levels of fatty acid–binding protein 4 (FABP4/aP2) in lesions from patients with recent symptoms of plaque instability compared to asymptomatic patients (array: FC = 2, P < 0.05; RT‐PCR: P < 0.05). At the mRNA level, FABP4/aP2 correlated with the cell markers CD36, CD68 and CD163 of monocyte/macrophage lineage as well as with CD4‐positive T cells. FABP4/aP2 mRNA expression was also correlated with enzymes of the leukotriene pathway, 5‐lipoxygenase and leukotriene A4 hydrolase. In addition, analysis of transcript profiles identified CD52 and adipophilin as the mRNAs with the highest correlation with FABP4/aP2. Expression of FABP4/aP2 by macrophages and CD52 by T cells in the lesion was confirmed by immunohistochemistry.
Conclusions.  Expression of FABP4/aP2 is increased at the mRNA level in unstable carotid plaques. Immunohistochemical analyses showed localization of FABP4/aP2 to macrophage populations. These FABP4/aP2‐positive macrophages constitute an important and prevalent phenotype and could provide a new link between scavenging‐mediated lipid uptake and cellular metabolic stress in plaque. In addition FABP4/aP2 correlates with other important signs of inflammation and plaque instability, such as T cells and leukotriene enzymes. Taken together, these results indicate that FABP4/aP2 is a key factor connecting vascular and cellular lipid accumulation to inflammation.