Phenotypic modulation of smooth muscle cells in atherosclerosis is associated with downregulation of LMOD1, SYNPO2, PDLIM7, PLN, and SYNM

Ljubica Perisic Matic, Urszula Rykaczewska, Anton Razuvaev, Maria Sabater-Lleal, Mariette Lengquist, Clint L. Miller, Ida Ericsson, Samuel Röhl, Malin Kronqvist, Silvia Aldi, Joelle Magné, Valentina Paloschi, Mattias Vesterlund, Yuhuang Li, Hong Jin, Maria Gonzalez Diez, Joy Roy, Damiano Baldassarre, Fabrizio Veglia, Steve E. HumphriesUlf De Faire, Elena Tremoli, Jacob Odeberg, Vladana Vukojevic, Janne Lehtiö, Lars Maegdefessel, Ewa Ehrenborg, Gabrielle Paulsson-Berne, Göran K. Hansson, Jan H N Lindeman, Per Eriksson, Thomas Quertermous, Anders Hamsten, Ulf Hedin

Research output: Contribution to journalArticlepeer-review

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 immunoprecipitationsequencing. 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.

Original languageEnglish
Pages (from-to)1947-1961
Number of pages15
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume36
Issue number9
DOIs
Publication statusPublished - Sep 1 2016

Keywords

  • Actin cytoskeleton
  • Atherosclerosis
  • Downregulation
  • Hyperplasia
  • Smooth muscle cells

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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