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Atherosclerosis journal highlights June issue 2017

Tuesday 20 June 2017   (0 Comments)
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Volume 261 Issue June 2017

By Simona Negrini and Arnold von Eckardstein (Editor–in-Chief).

Nucleic acids have become a prime target of personalized medicine, both for diagnostics and therapy. This issue of Atherosclerosis contains several articles on studies targeting nucleic acids, reaching from classical mutation analysis over quantification of mitochondrial DNA or microRNAs in blood or plasma, for diagnosis of aneurysm and coronary heart disease risk, to interference with specific microRNAs for therapy of atherosclerosis.

Issue highlights


    Highlighted articles

    Identifying low density lipoprotein cholesterol associated variants in the Annexin A2 (ANXA2) gene

    Annexin-A2 (AnxA2) is an endogenous inhibitor of proprotein convertase subtilisin/kexin type-9 (PCSK9). The repeat-one (R1) domain of AnxA2 binds to PCSK9, blocking its ability to promote degradation of low-density lipoprotein cholesterol-receptors (LDL-R) and thereby regulates low-density lipoprotein cholesterol (LDL-C) levels. Fairoozy et al. aimed at identifying variants in the ANXA2 gene influencing LDL-C levels and at determining the molecular mechanisms of their effects.

    The ANXA2 single nucleotide polymorphism (SNP) genotype-phenotype association was examined using the Second-Northwick-Park Heart Study (NPHSII) (n∼2700) and the UCL-LSHTM-Edinburgh-Bristol (UCLEB) consortium (n∼14,600).

    The ANXA2-R1 domain coding-SNP rs17845226 (V98L) associated with LDL-C, homozygotes for the minor allele having ≈18.8% higher levels of LDL-C, and higher risk of coronary heart disease (CHD). The SNP is in modest linkage disequilibrium with two intergenic SNPs, rs17191344 and rs11633032. Both SNPs showed allele-specific protein binding, and the minor alleles caused significant reduction in reporter gene expression. In the expression quantitative trait loci (eQTL) study, minor allele homozygotes have significantly lower levels of ANXA2-mRNA expression.

    Both rs11633032 and rs17191344 SNPs are functional variants, where the minor alleles create repressor-binding protein sites for transcription factors that contribute to reduced ANXA2 gene expression. Lower AnxA2 levels could increase plasma levels of PCSK9 and thus, increase LDL-C levels and risk of CHD. These finding support, for the first time in humans, previous observations in mouse models that changes in the levels of AnxA2 directly influence plasma LDL-C levels, and thus implicate this protein as a potential therapeutic target for LDL-C lowering.

    Association between peripheral blood cells mitochondrial DNA content and severity of coronary heart disease

    Leukocyte mitochondrial DNA (mtDNA) content reflects the oxidant-induced cell damage, which has been observed in a wide range of cardiovascular diseases. However, whether it correlates with coronary heart disease (CHD), which closely relates to oxidative stress, has never been elucidated before. Liu and colleagues aimed at exploring the association between mtDNA content and the presence and severity of CHD.

    The authors performed a clinical trial on 400 individuals (290 with CHD and 110 controls). The relative content of mtDNA in peripheral blood cells (PBCs) was measured by quantitative real-time PCR. The Gensini score was used to evaluate the severity of coronary stenotic lesions. The association between CHD risk and mtDNA content was assessed using unconditional multivariate logistic regression analysis.

    Compared to controls, CHD patients had lower mtDNA content and the mtDNA levels significantly decreased following an increasing Gensini score. By using the first (highest mtDNA content) quartile of mtDNA content of controls as reference, the adjusted ORs for individuals in the second, third and highest quartile of mtDNA content were 1.78, 2.21 and 4.83, respectively.

    These preliminary results suggest that expression of mtDNA may be associated with atherogenesis. The mtDNA content may serve as a novel biomarker in predicting CHD development and quantifying the severity of CHD.

    A systematic review investigating the association of microRNAs with human abdominal aortic aneurysms

    There is increasing interest in identifying novel methods for abdominal aortic aneurysm (AAA) diagnosis. Non-coding RNA molecules such as microRNAs (miRNAs) are stable within the circulation and may serve as biomarkers for AAA. With this systematic review of the current literature, Iyer and colleagues aimed at identifying miRNAs associated with a diagnosis of human AAA.

    The authors performed a systematic search of the MEDLINE and EMBASE databases for studies assessing miRNA expression in abdominal aortic tissue or circulating blood from human AAA cases compared to non-aneurysmal controls.

    Fifteen studies were included, quality assessment of data from included studies was performed independently by two reviewers. The authors reported that eleven studies obtained aortic tissue samples from 195 AAA cases and 104 controls with normal aortas. Nine studies obtained circulating blood samples from 526 AAA cases and 441 controls. miR-21 was differentially expressed in AAA tissue in five separate studies, with four studies reporting upregulation and one reporting downregulation. Seven other miRNAs were differentially expressed in AAA tissue in two separate studies. Fifteen circulating miRNAs were differentially expressed in two or more separate studies. miR-155 and miR-29b were the only miRNAs differentially expressed in two separate tissue- and blood-based studies. Eleven studies offered mechanistic explanations of the role of miRNAs in AAA pathology through exploration of gene targets. Three studies assessed the diagnostic potential of circulating miRNAs with receiver operating characteristic curves. Only one study assessed the prognostic potential of circulating miRNAs in predicting AAA growth.

    Several miRNAs have been found to be associated with human AAA. However, their utility as AAA biomarkers requires further investigation.

    Whole blood sequencing reveals circulating microRNA associations with high-risk traits in non-ST-segment elevation acute coronary syndrome

    Although circulating microRNA (miRNAs) have emerged as biomarkers predicting mortality in acute coronary syndrome (ACS), more data are needed to understand these mechanisms. Mapping miRNAs to high-risk traits may identify miRNAs involved in pathways conferring risk for poor outcome in ACS. Wang et al. aimed at investigating the relationship between circulating miRNAs and high-risk traits in non-ST-segment elevation acute coronary syndrome (NSTE-ACS).

    To this purpose, whole-genome miRNA sequencing was performed on RNA extracted from whole blood of 199 patients with NSTE-ACS. Generalized linear models were used to test the association of miRNAs and 13 high-risk clinical traits, including the Global Registry of Acute Coronary Events (GRACE) score, a widely validated risk score for mortality in NSTE-ACS.

    The authors observed 205 nominally significant miRNA-risk factor associations. Significant associations occurred most frequently with chronic heart failure (HF) (43 miRs), GRACE risk score (30 miRs), and renal function (32 miRs). In a hierarchical cluster analysis, chronic HF and GRACE risk score clustered most tightly together, sharing 14 miRNAs with matching fold-change direction. Controlling for a false discovery rate of 5%, chronic HF was significantly associated with lower circulating levels of miR-3135b, miR-126-5p, miR-142-5p and miR-144-5p, while increasing GRACE risk score inversely correlated with levels of miR-3135b and positively correlated with levels of miR-28-3p.

    These results showed that circulating miRs clustered around chronic heart failure and the GRACE risk score, two powerful traits for mortality risk in NSTE-ACS. Mapping miRNAs to high-risk traits may identify miRNAs involved in pathways conferring risk for poor outcome in ACS.

    Inhibition of 14q32 microRNA miR-495 reduces lesion formation, intimal hyperplasia and plasma cholesterol levels in experimental restenosis

    Restenosis occurs regularly in patients treated for coronary artery disease and peripheral arterial disease. Welten at al. aimed at investigating the role of 14q32 microRNAs in intimal hyperplasia and accelerated atherosclerosis: two major contributors to restenosis. The authors previously showed that inhibition of 14q32 microRNAs leads to increased post-ischemic neovascularization, and microRNA miR-494 decreases atherosclerosis, while increasing plaque stability. Based on these observations, they hypothesized that 14q32 microRNAs inhibition has beneficial effects on intimal hyperplasia, as well as accelerated atherosclerosis.

    Non-constrictive cuffs were placed around both femoral arteries of C57BL/6J mice to induce intimal hyperplasia. Accelerated atherosclerotic plaque formation was induced in hypercholesterolemic ApoE−/− mice by placing semi-constrictive collars around both carotid arteries. 14q32 microRNAs miR-329, miR-494 and miR-495 were inhibited in vivo using Gene Silencing Oligonucleotides (GSOs).

    The authors showed that GSO-495 administration led to a 32% reduction of intimal hyperplasia. Moreover, the number of macrophages in the arterial wall of GSO-495-treated mice was reduced by 55%. Inhibition of miR-329 and miR-494 had less effects on intimal hyperplasia. GSO-495 administration also decreased atherosclerotic plaque formation by 52% and plaques of GSO-495-treated animals showed a more stable phenotype. Finally, cholesterol levels were also decreased in GSO-495-treated animals, via reduction of the VLDL fraction.

    GSO-495 administration decreased the primary outcomes, namely intimal hyperplasia, and accelerated atherosclerosis, and favourably affected multiple secondary outcomes, including macrophage influx, plaque stability and total plasma cholesterol levels. These results suggest that 14q32 microRNA miR-495 is a promising target for prevention of restenosis.

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