Gene expression signatures, pathways and networks in carotid atherosclerosis

Perisic, Ljubica; Aldi, Silvia; Sun, Yuhang; Folkersen, Lasse; Razuvaev, Anton; Roy, Joy; Lengquist, Mariette; Akesson, S.; Wheelock, Craig E.; Maegdefessel, Lars; Gabrielsen, Anders; Odeberg, Jacob; Hansson, Göran K.; Paulsson-Berne, Gabrielle; Hedin, Ulf

doi:10.1111/joim.12448

Cited by 122 publications

(129 citation statements)

References 76 publications

(107 reference statements)

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“…Antibody specificity was confirmed using isotype control and by preincubating the anti-CD47 Ab with recombinant CD47 antigen (R&D Systems) in a 1:5 ratio for 16h at 4°C before application. High resolution imaging of the carotid sections was performed as previously described 37 .…”

Section: Methodsmentioning

confidence: 99%

CD47-blocking antibodies restore phagocytosis and prevent atherosclerosis

Kojima

Volkmer

McKenna

et al. 2016

Nature

512

497

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Summary Atherosclerosis is the disease process underlying heart attack and stroke1. Advanced lesions at risk for rupture are characterized by the pathological accumulation of diseased vascular cells and apoptotic cellular debris2. Why these cells are not cleared remains unknown3. Here we show that atherogenesis is associated with upregulation of CD47, a key ‘don’t eat me’ molecule known to render malignant cells resistant to programmed cell removal (PrCR), or ‘efferocytosis’4–7. We find that administration of CD47 blocking antibodies reverses this defect in efferocytosis, normalizes the clearance of diseased vascular tissue, and ameliorates atherosclerosis in multiple mouse models. Mechanistic studies implicate the pro-atherosclerotic factor TNF-α as a fundamental driver of impaired PrCR, explaining why this process is compromised in vascular disease. Similar to recent observations in cancer5, impaired efferocytosis appears to play a pathogenic role in cardiovascular disease, but is not a fixed defect and may represent a novel therapeutic target.

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Section: Methodsmentioning

confidence: 99%

CD47-blocking antibodies restore phagocytosis and prevent atherosclerosis

Kojima

Volkmer

McKenna

et al. 2016

Nature

512

497

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“…Next, expression of miR-210 target genes in carotid plaques was examined in previously published BiKE data sets (Gene Expression Omnibus accession number GSE21545), 14 to identify significantly deregulated genes comparing plaques versus control arteries and plaque from symptomatic versus asymptomatic subjects. Finally, miR-210 target gene expression in plaques was validated by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) analysis (Methods in the Online Data Supplement).…”

Section: Selection Of Mir-210 Targets For Functional Analysismentioning

confidence: 99%

MicroRNA-210 Enhances Fibrous Cap Stability in Advanced Atherosclerotic Lesions

Eken

Jin

Chernogubova

et al. 2017

Circulation Research

111

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Stroke is the second most common cause of death 2 and major cause of disability worldwide, 2 with survivors often depending on lifelong care. Carotid stenosis is the second most common predecessor of ischemic stroke, 3 and carotid endarterectomy (CEA; and to a lesser extent carotid artery stenting) are accepted as secondary, but also primary preventive therapy. 2,4,5 With new imaging techniques, vulnerable plaques at risk of rupture can be identified with increasing accuracy, 6 but in the majority of cases, the perioperative surgical risk of ≈3% still outweighs the risk of plaque rupture in asymptomatic carotid stenosis carriers.7 As a result, CEA and carotid artery stenting are currently unfavorable for most of these individuals.8 Detection and stabilization of a vulnerable plaque by influencing the local disease process biologically would provide a sophisticated solution for asymptomatic plaque carriers at risk of stroke. Molecular Medicine© 2016 American Heart Association, Inc. Conclusions: An unstable carotid plaque at risk of stroke is characterized by low expression of miR-210. miR-210 contributes to stabilizing carotid plaques through inhibition of APC, ensuring smooth muscle cell survival. We present local delivery of miR-210 as a therapeutic approach for prevention of atherothrombotic vascular events.

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“…[27][28][29][30] Microarray data from plaque tissue in the Biobank of Karolinska Endarterectomies (BiKE) cohort, available for n=125 patients, were analyzed for association with rs17293632C>T. Because neither this SNP nor rs56062135C>T were present on the chip, rs16950687A>G (D′ 0.949; r 2 0.859 with rs17293632; D′ 1; r 2 0.953 with rs56062135) was used as a proxy SNP. As shown, rs16950687A>G was significantly associated with SMAD3 mRNA levels in carotid lesions (P<0.05; Figure 3B).…”

Section: Turner Et Al Functional Analysis Of the Smad3 Locus For Cad 977mentioning

confidence: 99%

Functional Analysis of a Novel Genome-Wide Association Study Signal in SMAD3 That Confers Protection From Coronary Artery Disease

Turner

Martinuk

Silva

et al. 2016

ATVB

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Objective-A recent genome-wide association study meta-analysis identified an intronic single nucleotide polymorphism in SMAD3, rs56062135C>T, the minor allele (T) which associates with protection from coronary artery disease. Relevant to atherosclerosis, SMAD3 is a key contributor to transforming growth factor-β pathway signaling. Here, we seek to identify ≥1 causal coronary artery disease-associated single nucleotide polymorphisms at the SMAD3 locus and characterize mechanisms whereby the risk allele(s) contribute to coronary artery disease risk. Approach and Results-By genetic and epigenetic fine mapping, we identified a candidate causal single nucleotide polymorphism rs17293632C>T (D′, 0.97; r 2 , 0.94 with rs56062135) in intron 1 of SMAD3 with predicted functional effects. We show that the sequence encompassing rs17293632 acts as a strong enhancer in human arterial smooth muscle cells. The common allele (C) preserves an activator protein (AP)-1 site and enhancer function, whereas the protective (T) allele disrupts the AP-1 site and significantly reduces enhancer activity (P<0.001). Pharmacological inhibition of AP-1 activity upstream demonstrates that this allele-specific enhancer effect is AP-1 dependent (P<0.001). Chromatin immunoprecipitation experiments reveal binding of several AP-1 component proteins with preferential binding to the (C) allele. We show that rs17293632 is an expression quantitative trait locus for SMAD3 in blood and atherosclerotic plaque with reduced expression of SMAD3 in carriers of the protective allele. Finally, siRNA knockdown of SMAD3 in human arterial smooth muscle cells increases cell viability, consistent with an antiproliferative role. Phosphorylated SMAD3 then forms a complex with the common SMAD4 that subsequently translocates to the nucleus and regulates transcription. 6,7 Relevant to a role in atherosclerosis, in systems genetics analysis of multiple GWAS, we identified TGF-β signaling and SMAD transcriptional activities as enriched pathways for CAD association. 8 However, despite extensive data on the functions of TGF-β with respect to atherosclerosis, 9,10 the roles of SMAD proteins particularly SMAD3 and SMAD3 signaling are less well-understood. Conclusions-TheSMAD3 is expressed at low levels in healthy human aorta by immunohistochemistry and quantitative reverse transcription polymerase chain reaction (PCR).11 There is, however, a marked increase in SMAD3 and other SMAD proteins in fibrofatty lesions, with expression mostly limited to CD68-positive macrophages/macrophage-derived foam cells in these samples. Conversely, in fibrous atherosclerotic plaques, there are high levels of SMAD3 in vascular smooth muscle cells (SMCs), suggesting that the role of SMAD3 in atherosclerosis depends on cell type and stage of atherosclerosis.11 Higher SMAD3 expression in SMCs of the fibrous plaque coincides with TGF-β-mediated synthesis of collagen and other extracellular matrix proteins, which contribute to plaque stability.12 Rare SMAD3 mutations cause aneurysms-osteoarthritis syn...

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Gene expression signatures, pathways and networks in carotid atherosclerosis

Cited by 122 publications

References 76 publications

CD47-blocking antibodies restore phagocytosis and prevent atherosclerosis

CD47-blocking antibodies restore phagocytosis and prevent atherosclerosis

MicroRNA-210 Enhances Fibrous Cap Stability in Advanced Atherosclerotic Lesions

Functional Analysis of a Novel Genome-Wide Association Study Signal in SMAD3 That Confers Protection From Coronary Artery Disease

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