Trends in Endocrinology & Metabolism
ForumAtherosclerosis Is an Epigenetic Disease
Introduction
Atherosclerotic plaque development and rupture are responsible for major clinical cardiovascular events (such as myocardial infarction and stroke) worldwide [1]. Understanding the molecular mechanisms that drive atherosclerosis and plaque destabilization is indispensable for developing new therapeutic strategies [1]. Since 1990s, atherosclerosis has been considered as a chronic inflammatory disease. It initially starts from endothelial response to injury, followed by lipid buildup in the vessel wall, impaired resolution of persistent inflammation, as well as plaque rupture and thrombosis 1, 2, 3, 4. Based on the ‘lipid’ and ‘inflammation’ hypothesis of atherosclerosis development, lipid-lowering statins and anti-inflammatory agents are the cornerstone of atherosclerosis management. However, residual cardiovascular risk in certain groups of patients remains very high and some patients have poor responsiveness to statins [5]. Thus, additional therapies are needed. More recently, the role of epigenetics in atherosclerosis has been increasingly recognized [6]. Epigenetic mechanisms include DNA methylation/demethylation, histone methylation/demethylation, histone acetylation/deacetylation, and noncoding RNAs [6]. Increasing evidence has shown that these epigenetic processes are involved in the initiation and progression of atherosclerosis. More importantly, epigenetic processes, DNA and histone modification in particular, have specific ‘writers’ (introducing epigenetic marks) and ‘erasers’ (removing epigenetic marks) that regulate gene expression. Epigenetic processes are highly dynamic, reversible, and hence drug targetable, providing an excellent opportunity to treat atherosclerosis by targeting these epigenetic processes [7] (Figure 1).
Section snippets
Epigenetic Mechanisms of Atherosclerosis
The complex of DNA and histone proteins (H2A, H2B, H3, and H4) forms the chromatin, which is the basic unit critical for gene transcription/silencing, signal transduction, DNA repair, and DNA replication, etc. [8]. Chromatin can undergo a remodeling process by switching from a tightly packed condensed state (heterochromatin) to an open conformation state (euchromatin), allowing nuclear transcription factors or DNA-binding proteins to access DNA and thus alter gene expression [8]. Chromatin
Therapeutic Potential of Epigenetic Cardiovascular Drugs
The epigenetic mechanisms of atherosclerosis suggest the necessities to develop small-molecule epigenetic drugs targeting chromatin architecture to combat atherosclerosis (Table 1). These epigenetic drugs are already widely used in cancer therapy or cancer-related clinical trials, such as HDAC inhibitors, sirtuin activating compounds (such as resveratrol), DNA methylation inhibitors (such as 5-azacytidine and its nucleoside analogs), and histone methylation inhibitors (such as EZH2 inhibitors).
Acknowledgments
The authors are grateful to researchers in the field whose original work cannot be cited due to reference and space limitations. Figures were prepared with Servier Medical Art (https://smart.servier.com/). This work was supported by grants from the National Institutes of Health (NIH; HL09502, HL114570, HL128363 and HL130167 to Z.G.J.) and the American Heart Association (17GRNT33660671 to Z.G.J.).
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