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Highlighted articles February/March 2019

Volume 281, Issue February 2019
Volume 282, Issue March 2019

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

The February and March issues were published very close to each other so that this newsletter selects articles of both. A review series guest-edited by Menno De Winther and Geesje Dallinga-Thie is centered around the novel developments in gene regulation by epigenetics and non-coding RNAs to help understand the underlying pathobiology of cardiovascular disease. The two issues also contain original work on noncoding RNAs.

Issue highlights

Articles on:

 

Highlighted articles

Epigenetic processing in cardiometabolic disease

Albeit a consistent body of evidence supports the notion that genes influence cardiometabolic features and outcomes, the “non-genetic regulation” of this process is gaining increasing attention.
Plastic chemical changes of DNA/histone complexes – known as epigenetic changes – critically determine gene activity by rapidly modifying chromatin accessibility to transcription factors.
In this review, Costantino and colleagues describe the role of chromatin modifications as regulator of gene transcription in adipogenesis, insulin resistance, macrophage polarization, immuno-metabolism, endothelial dysfunction and metabolic cardiomyopathy.
Epigenetic processing participates in the dynamic interplay among different organs in the cardiometabolic patient. Cell-specific epigenetic information could advance our understanding of cardiometabolic processes, thus leading to individualized risk assessment and personalized therapeutic approaches in patients with cardiometabolic disturbances.
The development of new chromatin modifying drugs indicates that targeting epigenetic changes is a promising approach to reduce the burden of cardiovascular disease in this setting.

Nature and nurture of tissue-specific macrophage phenotypes

Macrophages are key players in immunity and tissue homeostasis but can also contribute to a diverse range of human diseases, including cardiovascular diseases.
Enhancers, cis-acting DNA elements regulating gene activity, have been shown to be crucial to control macrophage development and function. The selection and activities of macrophage-specific enhancers are regulated by the combined actions of lineage determining transcription factors (LDTFs) and signal dependent transcription factors (SDTFs) that are specified by developmental origin and tissue-specific signals.
In this review, Hoeksema and Glass discuss recent work on how environmental factors affect the activation status of enhancers and can lead to long-lasting epigenetic changes resulting in innate immune memory. They also discuss how non-coding genetic variation affects gene expression by altering transcription factor binding through local and domain-wide mechanisms.
These findings have implications for interpretation of non-coding risk alleles that are associated with human disease and efforts to target macrophages for therapeutic purposes.

DNA methylation processes in atherosclerotic plaque

Accumulating evidence suggests that epigenetic modifications are actively reshaping pathological processes (e.g. dedifferentiation of smooth muscle cells, accumulation of senescent cells) in cardiovascular disease (CVD).
Senescence of vascular cells in ageing arteries not only counteracts regenerative processes but also exacerbates atherogenesis. Epigenome modifications include changes in DNA methylation, histone code and expression of non-coding RNAs. DNA methylation is a major epigenetic regulator modulating cell-type specific gene expression in mural cells, but there is some controversy regarding how to interpret the role of DNA hyper- and hypomethylation in CVD pathology.
DNA hypomethylation (loss of methyl cytosines) appears to predominate in atherosclerosis, while a few genes become more methylated (i.e. hypermethylated) as the disease progresses in medium-sized and large arteries. The actual time-course of atherosclerosis-linked changes in genomic DNA methylation is still poorly studied.
In this review, Aavik et al. highlight recent novel findings, which link alterations in DNA methylation to atherogenesis and describe new potential approaches for novel treatments.

Long intergenic noncoding RNAs in cardiovascular diseases: Challenges and strategies for physiological studies and translation

Long intergenic noncoding RNAs (lincRNAs) are increasingly recognized as important mediators of many biological processes relevant to human pathophysiologies, including cardiovascular diseases.
In vitro studies have provided important knowledge of cellular functions and mechanisms for an increasing number of lincRNAs. Dysregulated lncRNAs have been associated with cell fate programming and development, vascular diseases, atherosclerosis, dyslipidemia and metabolic syndrome, and cardiac pathological hypertrophy.
However, functional interrogation of individual lincRNAs in physiological and disease states is largely limited. The complex nature of lincRNA actions and poor species conservation of human lincRNAs pose substantial challenges to physiological studies in animal model systems and in clinical translation. In this review, Zhang et al. summarize recent findings of specific lincRNA physiological studies, including MALAT1, MeXis, Lnc-DC and others, in the context of cardiovascular diseases, examine complex mechanisms of lincRNA actions, review in vivo research strategies to delineate lincRNA functions and highlight challenges and approaches for physiological studies of primate-specific lincRNAs.

Potential epigenetic therapeutics for atherosclerosis treatment

The pivotal role of epigenetic changes in the control of gene expression has been profiled in several diseases, such as cancer and inflammatory disorders.
In the last decade, increasing evidence has also linked aberrant epigenetic modulation as a contributor to cardiovascular disease (CVD) development. Differential profiles of DNA methylation, histone methylation and acetylation have consistently been observed in tissues and cells (comprising the aortic lesions, vascular endothelium and monocytes) of patients with CVD. This highlights the therapeutic potential of epigenetic drugs for cardiovascular treatment. In this review, Nicorescu et al. focus on potential epigenetic compounds that could be used to prevent or treat atherosclerosis based on the epigenetic concept.

LncRNA HOXA-AS2 represses endothelium inflammation by regulating the activity of NF-κB signaling

Endothelium inflammation, which can lead to endothelial activation and dysfunction, is widely accepted as the major event in multiple vascular disorders. Long non-coding RNAs (LncRNAs) are a set of non-coding transcripts, which generally are more than 200 bases in length. Some lncRNAs were found to be significantly involved in the regulation of endothelial inflammation and vascular diseases. In this study, Zhu et al. assess the role of lncRNA HOXA-AS2, previously reported to be involved in multiple inflammation-linked cancers, in endothelium inflammation and related vascular diseases.

High throughput mRNA sequencing was performed to establish expression profiles after HOXA-AS2 depletion. Total RNAs of human peripheral blood mononuclear cells (from a normal control group and an experimental group with carotid artery atherosclerosis) was extracted and subject to qRT-PCR to assay the correlation between HOXA-AS2 expression and inflammatory vascular diseases.
The results showed that inhibition of HOXA-AS2 can induce activation of NF-κB signalling and the subsequent inflammatory response. NF-κB inversely activates the transcription elongation of HOXA-AS2 by establishing a NF-κB/HOXA-AS2 negative feedback loop.

In summary, HOXA-AS2 is a critical repressor of endothelium inflammation. HOXA-AS2 may serve as a crucial therapeutic target for various vascular disorders significantly associated with endothelium inflammation.

Dual inhibition of endothelial miR-92a-3p and miR-489-3p reduces renal injury-associated atherosclerosis

Cardiovascular disease (CVD) is the leading cause of death in chronic kidney disease (CKD) patients, however, the underlying mechanisms that link CKD and CVD are not fully understood, and limited treatment options exist in this high-risk population. microRNAs (miRNA) are critical regulators of gene expression for many biological processes in atherosclerosis, including endothelial dysfunction and inflammation. Among them, miR-92a-3p was identified as a pro-atherogenic miRNA in endothelial cells. Recently, miR-92a-3p was also linked to CKD: miR-92a-3p levels were found to be increased in serum from CKD subjects and aortic miR-92a-3p levels were reported to be increased in rats with adenine-induced CKD. Thus, inhibition of endothelial miR-92a-3p has great potential as a therapeutic target to treat atherosclerosis in the context of CKD. However, the potential of miR-92a-3p as a therapeutic target for CKD-associated atherosclerosis has not been investigated so far. In this study, Wiese et al. hypothesized that renal injury-induced endothelial miRNAs promote atherosclerosis.

To test this hypothesis, aortic endothelial miRNAs were analyzed in Apoe −/- mice with renal damage (5/6Nx) by real-time PCR. Endothelial miR-92a-3p and miR-489-3p (also linked to kidney damage) were inhibited by locked-nucleic acid (LNA) miRNA inhibitors complexed to high density lipoproteins (HDL).

Renal injury significantly increased endothelial miR-92a-3p levels in Apoe−/-; 5/6Nx mice. In these mice, dual inhibition of miR-92a-3p and miR-489-3p significantly reduced the atherosclerotic lesion area by 28.6%. Moreover, dual miRNA inhibition significantly altered TGFβ signalling pathway and STAT3 transcriptional activity. In this setting, among the differentially expressed genes, Tgfb2 and Fam220a (a negative regulator of STAT3) were identified and subsequently validated as direct targets of miR-489-3p and miR-92a-3p, respectively.

These results support endothelial miRNAs as therapeutic targets and dual miRNA inhibition as viable strategy to reduce CKD-associated atherosclerosis.

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