Dataset Information

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

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.

SUBMITTER: Perisic Matic L

PROVIDER: S-EPMC8991816 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Publications

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

Perisic Matic Ljubica L Rykaczewska Urszula U Razuvaev Anton A Sabater-Lleal Maria M Lengquist Mariette M Miller Clint L CL Ericsson Ida I Röhl Samuel S Kronqvist Malin M Aldi Silvia S Magné Joelle J Paloschi Valentina V Vesterlund Mattias M Li Yuhuang Y Jin Hong H Diez Maria Gonzalez MG Roy Joy J Baldassarre Damiano D Veglia Fabrizio F Humphries Steve E SE de Faire Ulf U Tremoli Elena E Odeberg Jacob J Vukojević Vladana V Lehtiö Janne J Maegdefessel Lars L Ehrenborg Ewa E Paulsson-Berne Gabrielle G Hansson Göran K GK Lindeman Jan H N JH Eriksson Per P Quertermous Thomas T Hamsten Anders A Hedin Ulf U

Arteriosclerosis, thrombosis, and vascular biology 20160728 9

<h4>Objective</h4>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.<h4>Approach and results</h4>Muscle contraction, muscle development, and actin cytoskeleton were the most downregulated pathways (false discovery rate=6.99e-21, 1.66e-6, 2.54e-10 ...[more]

PMID: 27470516

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Dataset Information

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

Objective

Approach and results

Conclusions

Publications

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

Similar Datasets

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