Elsevier

Atherosclerosis

Volume 212, Issue 1, September 2010, Pages 16-29
Atherosclerosis

Review
Genetic and epigenetic mechanisms and their possible role in abdominal aortic aneurysm

https://doi.org/10.1016/j.atherosclerosis.2010.02.008Get rights and content

Abstract

Abdominal aortic aneurysm (AAA) is a common disease associated with significant cardiovascular morbidity and mortality. The pathogenesis of AAA is poorly defined, making targeting of new therapies problematic. Current evidence favours an interaction of multiple environmental and genetic factors in the initiation and progression of AAA. Epigenetics is the term used to define the properties of the genome that are not explained by the primary sequence, but are due to the modifications of DNA and/or associated proteins. Previous research indicates the association of gene specific promoter DNA hyper-methylation and global DNA hypo-methylation with atherosclerosis. Evidence also suggests an important role for epigenetic processes such as histone acetylation in cardiovascular diseases including atherosclerosis and restenosis. Altered DNA methylation or histone acetylation occur in inflammation, cellular proliferation and remodelling processes and therefore maybe relevant to the pathology of AAA. Important risk factors for AAA, including cigarette smoking, older age, male gender and hypertension, have been linked with epigenetic effects and thus could act in this way to promote AAA. In this review, we discuss the potential role of epigenetic mechanisms in AAA. Since epigenetic alterations are to some extent reversible, further study of this area may identify new treatment targets for AAA.

Introduction

Gene expression patterns can be regulated at the genetic level by mutations or polymorphisms which affect the coding as well as non-coding sequence and also at the epigenetic level. Regulations of gene expression by epigenetic mechanisms are crucial determinants of cellular behaviour. Previous research suggests that environmental risk factors may promote complex diseases by stimulating a variety of epigenetic changes (reviewed in [1], [2]). Epigenetic processes modulate the chromosomal organisation without altering the actual DNA sequence, and thereby contribute to the modulation of gene expression [1]. Epigenetic control of gene expression involves chromatin modification processes such as DNA methylation and several histone modifications including acetylation, methylation, phosphorylation and ubiquitinisation [1]. DNA methylation patterns are stably inherited upon mitosis in an adult cell, but deviations from the normal DNA methylation pattern may contribute to aging related diseases such as cancer and cardiovascular diseases [3]. The contribution of epigenetics to atherosclerosis has gained prominence recently due evidence that certain dietary components and smoking modulate DNA methylation in the arterial wall [4], [5]. Since the methylation status of a gene or a change in chromatin structure is reversible, epigenetics has recently emerged as a potential molecular target for intervention [3].

Currently the contribution of epigenetic factors to the development of abdominal aortic aneurysm (AAA) has been little investigated. Histone acetylation levels have been demonstrated to vary in association with inflammation, proliferation and remodelling processes and thereby linked to atherosclerosis and restenosis [6]. In this review, we discuss the potential contribution of epigenetic mechanisms to AAA pathogenesis.

Section snippets

Abdominal aortic aneurysm

AAA (OMIM: 100070) is most commonly defined by an enlargement of the abdominal aorta to ≥30 mm, although other definitions also exist. AAA is associated with an increased risk of aortic rupture and also a high rate of other cardiovascular events, such as myocardial infarction, stroke and lower limb ischemia [7]. AAA affects approximately 5–7% of men and 1% of women over the age of 65, and is more common in smokers, subjects with dyslipidemia and hypertension [8], [9].

At present the only accepted

Genetic determinants of AAA

Up to 19% of patients report one or more first-degree relatives with an AAA suggesting a genetic predisposition for the condition [19], [20]. In a nationwide survey in Sweden, it was observed that the relative risk of developing AAA for first-degree relatives to persons diagnosed with AAA was approximately doubled (OR = 1.9; 95% CI, 1.6–2.2, p < 0.0001) compared to persons with no family history [21]. Previous segregation studies using first degree relatives of AAA patients (91 probands) have

Overview of epigenetic mechanisms

DNA is packaged into chromatin, and the chromatin complex consists of DNA, histones and other chromosomal proteins. The fundamental unit of chromatin is a nucleosome octamer which comprises of 147 base pairs of DNA wrapped around two copies of histone proteins H2A, H2B, H3, and H4 [53]. The nucleosomal array folds into a 30 nm solenoid fibre with the help of linker histones which further folds to form a higher-order chromatin structure (Fig. 1). Histone proteins are evolutionarily conserved,

The relevance of epigenetics to AAA

There has been very limited investigation of the role of epigenetic in AAA, with most of the current evidence having to be inferred from studies of atherosclerosis. Previously, atherosclerosis was considered to be the most important determinant of AAA development but recent opinion suggests that the association of intimal atheroma and aortic dilatation is on the basis of shared risk factors, such as age and smoking [15], [69], [70]. The association of DNA methylation with cardiovascular disease

Epigenetic therapy

Evidence suggests that epigenetic processes are reversible; hence proteins playing crucial role in various epigenetic processes have emerged as potential targets for pharmacological interventions. Currently two main epigenetic treatments are under consideration; HDAC inhibitors (HDACi) and DNA methylation inhibitors (Fig. 2a and b) [54].

Several HDAC inhibitors (HDACi) have been identified and have been shown to exhibit clinical activity against human neoplasms [142]. Most of the small molecule

Conclusions and future perspectives

Fig. 3 summarises the potential role of epigenetics in AAA, although there is currently little conclusive evidence. There are several lines of evidence that suggest an important role of altered histone acetylation levels and DNA methylation levels in processes critical in AAA initiation such as inflammation and matrix remodelling.

Also evidence from other cardiovascular diseases suggests the possible role played by epigenetic mechanisms in AAA. In a recent preliminary study in ascending aortic

Acknowledgments

Work carried out by the research team is funded by grants from the National Institute of Health, USA [RO1 HL080010]; The Townsville Hospital Private Practice Fund; and The National Health and Medical Research Council [project grants 540403, 540404 and 540405]. JG and PEN hold Practitioner Fellowships from the National Health and Medical Research Council, Australia [431503,458505].

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      Krishna et al., 2013 reviewed the role of homocysteine mediated DNA methylation and associated epigenetic changes in AAA, which appears to be important in disease [56]. However, due to the scarcity of research around the topic, much of the evidence for DNA methylation as a pathogenic mechanism of AAA has to be inferred from studies of atherosclerosis and hypertension, which share risk factors with AAA, and often co-exist with AAA [11,53,57]. Evidence can also be inferred from the molecular pathogenic mechanisms of AAA, in addition to major environmental risk factors.

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