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Arterioscler Thromb Vasc Biol. 2016 Sep;36(9):1947-61. doi: 10.1161/ATVBAHA.116.307893. Epub 2016 Jul 28.

Phenotypic Modulation of Smooth Muscle Cells in Atherosclerosis Is Associated With Downregulation of LMOD1, SYNPO2, PDLIM7, PLN, and SYNM.

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1
From the Departments of Molecular Medicine and Surgery (L.P.M., U.R., A.R., M.L., I.E., S.R., M.K., S.A., J.R., U.H.), Medicine (M.S.-L., J.M., V.P., Y.L., H.J., M.G.D., L.M., E.E., G.P.-B., G.K.H., P.E., A.H.), Division of Cardiovascular Epidemiology, Institute of Environmental Medicine (U.d.F.), and Department of Clinical Neuroscience, Center for Molecular Medicine (V.V.), Karolinska Institutet, Solna, Sweden; Division of Vascular Surgery, Stanford University, CA (C.L.M., T.Q.); Science for Life Laboratory, Solna, Sweden (M.V., J.L.); Dipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano, Italy (D.B., E.T.); Dipartimento di Scienze Cliniche e di Comunità, Centro Cardiologico Monzino, IRCCS, Milan, Italy (D.B., F.V., E.T.); British Heart Foundation Laboratories, Department of Medicine, University College of London, United Kingdom (S.E.H.); Department of Cardiology, Karolinska University Hospital Solna, Karolinska Institutet, Stockholm, Sweden (U.d.F.); Science for Life Laboratory, Department of Proteomics, Stockholm, Sweden (J.O.); and Department of Vascular Surgery, Leiden University Medical Center, The Netherlands (J.H.N.L.). Ljubica.Perisic@ki.se.
2
From the Departments of Molecular Medicine and Surgery (L.P.M., U.R., A.R., M.L., I.E., S.R., M.K., S.A., J.R., U.H.), Medicine (M.S.-L., J.M., V.P., Y.L., H.J., M.G.D., L.M., E.E., G.P.-B., G.K.H., P.E., A.H.), Division of Cardiovascular Epidemiology, Institute of Environmental Medicine (U.d.F.), and Department of Clinical Neuroscience, Center for Molecular Medicine (V.V.), Karolinska Institutet, Solna, Sweden; Division of Vascular Surgery, Stanford University, CA (C.L.M., T.Q.); Science for Life Laboratory, Solna, Sweden (M.V., J.L.); Dipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano, Italy (D.B., E.T.); Dipartimento di Scienze Cliniche e di Comunità, Centro Cardiologico Monzino, IRCCS, Milan, Italy (D.B., F.V., E.T.); British Heart Foundation Laboratories, Department of Medicine, University College of London, United Kingdom (S.E.H.); Department of Cardiology, Karolinska University Hospital Solna, Karolinska Institutet, Stockholm, Sweden (U.d.F.); Science for Life Laboratory, Department of Proteomics, Stockholm, Sweden (J.O.); and Department of Vascular Surgery, Leiden University Medical Center, The Netherlands (J.H.N.L.).

Abstract

OBJECTIVE:

Key augmented processes in atherosclerosis have been identified, whereas less is known about downregulated pathways. Here, we applied a systems biology approach to examine suppressed molecular signatures, with the hypothesis that they may provide insight into mechanisms contributing to plaque stability.

APPROACH AND RESULTS:

Muscle contraction, muscle development, and actin cytoskeleton were the most downregulated pathways (false discovery rate=6.99e-21, 1.66e-6, 2.54e-10, respectively) in microarrays from human carotid plaques (n=177) versus healthy arteries (n=15). In addition to typical smooth muscle cell (SMC) markers, these pathways also encompassed cytoskeleton-related genes previously not associated with atherosclerosis. SYNPO2, SYNM, LMOD1, PDLIM7, and PLN expression positively correlated to typical SMC markers in plaques (Pearson r>0.6, P<0.0001) and in rat intimal hyperplasia (r>0.8, P<0.0001). By immunohistochemistry, the proteins were expressed in SMCs in normal vessels, but largely absent in human plaques and intimal hyperplasia. Subcellularly, most proteins localized to the cytoskeleton in cultured SMCs and were regulated by active enhancer histone modification H3K27ac by chromatin immunoprecipitation-sequencing. Functionally, the genes were downregulated by PDGFB (platelet-derived growth factor beta) and IFNg (interferron gamma), exposure to shear flow stress, and oxLDL (oxidized low-density lipoprotein) loading. Genetic variants in PDLIM7, PLN, and SYNPO2 loci associated with progression of carotid intima-media thickness in high-risk subjects without symptoms of cardiovascular disease (n=3378). By eQTL (expression quantitative trait locus), rs11746443 also associated with PDLIM7 expression in plaques. Mechanistically, silencing of PDLIM7 in vitro led to downregulation of SMC markers and disruption of the actin cytoskeleton, decreased cell spreading, and increased proliferation.

CONCLUSIONS:

We identified a panel of genes that reflect the altered phenotype of SMCs in vascular disease and could be early sensitive markers of SMC dedifferentiation.

KEYWORDS:

actin cytoskeleton; atherosclerosis; downregulation; hyperplasia; smooth muscle cells

PMID:
27470516
DOI:
10.1161/ATVBAHA.116.307893
[Indexed for MEDLINE]
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