Correlations Between Clinical Variables and Gene-expression Profiles in Carotid Plaque Instability

Razuvaev, Anton; Ekstrand, Johan; Folkersen, Lasse; Agardh, Hanna E.; Markus, D.; Swedenborg, Jesper; Hansson, Göran K.; Gabrielsen, Anders; Paulsson-Berne, Gabrielle; Roy, Joy; Hedin, Ulf

doi:10.1016/j.ejvs.2011.05.023

Cited by 44 publications

(43 citation statements)

References 26 publications

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“…Pelisek et al also reported increased serum MMP-1 and MMP-7 levels in 64 patients with histological unstable atherosclerotic carotid lesions [7]. By using a microarray approach, Razuvaev et al examined mRNA levels in 106 carotid plaques, and showed that high expression of MMP-7 and MMP-9 was associated with an unstable plaque phenotype [18]. In the present study we extend these previous findings by showing increased MMP-7 levels systemically as well as within the atherosclerotic lesion in patients with carotid atherosclerosis with the most recent symptoms (i.e., within two months).…”

Section: Discussionmentioning

confidence: 99%

Matrix Metalloproteinase 7 Is Associated with Symptomatic Lesions and Adverse Events in Patients with Carotid Atherosclerosis

et al. 2014

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BackgroundAtherosclerosis is a major cause of cerebrovascular disease. Matrix metalloproteinases (MMPs) play an important role in matrix degradation within the atherosclerotic lesion leading to plaque destabilization and ischemic stroke. We hypothesized that MMP-7 could be involved in this process.MethodsPlasma levels of MMP-7 were measured in 182 consecutive patients with moderate (50–69%) or severe (≥70%) internal carotid artery stenosis, and in 23 healthy controls. The mRNA levels of MMP-7 were measured in atherosclerotic carotid plaques with different symptomatology, and based on its localization to macrophages, the in vitro regulation of MMP-7 in primary monocytes was examined.ResultsOur major findings were (i) Patients with carotid atherosclerosis had markedly increased plasma levels of MMP-7 compared to healthy controls, with particularly high levels in patients with recent symptoms (i.e., within the last 2 months). (ii) A similar pattern was found within carotid plaques with markedly higher mRNA levels of MMP-7 than in non-atherosclerotic vessels. Particularly high protein levels of MMP-7 levels were found in those with the most recent symptoms. (iii) Immunhistochemistry showed that MMP-7 was localized to macrophages, and in vitro studies in primary monocytes showed that the inflammatory cytokine tumor necrosis factor-α in combination with hypoxia and oxidized LDL markedly increased MMP-7 expression. (iv) During the follow-up of patients with carotid atherosclerosis, high plasma levels of MMP-7 were independently associated with total mortality.ConclusionOur findings suggest that MMP-7 could contribute to plaque instability in carotid atherosclerosis, potentially involving macrophage-related mechanisms.

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Section: Discussionmentioning

confidence: 99%

Matrix Metalloproteinase 7 Is Associated with Symptomatic Lesions and Adverse Events in Patients with Carotid Atherosclerosis

et al. 2014

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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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Section: Types Of Mmps and Their Involvement In Diseasesmentioning

confidence: 99%

“…MMP-7 has been reported to be increased by over 100-fold in patients with atherosclerotic carotid plaques and associated with plaque instability (82). In addition the upregulation of MMP-7 correlated with overexpression of inflammatory genes, RANKL and CD68 (82). In spontaneously hypertensive rats, the increase in MMP-7,-9 and elastase expressions has been demonstrated to cleave ICAM-1 in the glomeruli leading to renal inflammation (83).…”

Section: Types Of Mmps and Their Involvement In Diseasesmentioning

confidence: 99%

Regulation and involvement of matrix metalloproteinases in vascular diseases

et al. 2016

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Matrix metalloproteinases (MMPs) are a family of zinc dependent endopeptidases whose main function is to degrade and deposit structural proteins within the extracellular matrix (ECM). A dysregulation of MMPs is linked to vascular diseases. MMPs are classified into collagenases, gelatinases, membrane-type, metalloelastase, stromelysins, matrilysins, enamelysins, and unclassified subgroups. The production of MMPs is stimulated by factors such as oxidative stress, growth factors and inflammation which lead to its up- or down-regulation with subsequent ECM remodeling. Normally, excess activation of MMPs is controlled by their endogenous inhibitors, tissue inhibitors of metalloproteinases (TIMPs). An imbalance of MMPs and TIMPs has been implicated in hypertension, atherosclerotic plaque formation and instability, aortic aneurysms and varicose vein wall remodeling. Also, recent evidence suggests epigenetic regulation of some MMPs in angiogenesis and atherosclerosis. Over the years, pharmacological inhibitors of MMPs have been used to modify or prevent the development of the disease with some success. In this review, we discuss recent advances in MMP biology, and their involvement in the manifestation of vascular disease.

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Correlations Between Clinical Variables and Gene-expression Profiles in Carotid Plaque Instability

Abstract: Here, we demonstrate that gene-expression profiles reflect clinical parameters. Our results suggest that microarray technology and clinical variables can be used for the future identification of central molecular pathways in plaque instability.

Cited by 44 publications

References 26 publications

Matrix Metalloproteinase 7 Is Associated with Symptomatic Lesions and Adverse Events in Patients with Carotid Atherosclerosis

Matrix Metalloproteinase 7 Is Associated with Symptomatic Lesions and Adverse Events in Patients with Carotid Atherosclerosis

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

Regulation and involvement of matrix metalloproteinases in vascular diseases

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