Epigenetics and cardiovascular disease - PubMed (original) (raw)

Review

Epigenetics and cardiovascular disease

José M Ordovás et al. Nat Rev Cardiol. 2010 Sep.

Abstract

Despite advances in the prevention and management of cardiovascular disease (CVD), this group of multifactorial disorders remains a leading cause of mortality worldwide. CVD is associated with multiple genetic and modifiable risk factors; however, known environmental and genetic influences can only explain a small part of the variability in CVD risk, which is a major obstacle for its prevention and treatment. A more thorough understanding of the factors that contribute to CVD is, therefore, needed to develop more efficacious and cost-effective therapy. Application of the 'omics' technologies will hopefully make these advances a reality. Epigenomics has emerged as one of the most promising areas that will address some of the gaps in our current knowledge of the interaction between nature and nurture in the development of CVD. Epigenetic mechanisms include DNA methylation, histone modification, and microRNA alterations, which collectively enable the cell to respond quickly to environmental changes. A number of CVD risk factors, such as nutrition, smoking, pollution, stress, and the circadian rhythm, have been associated with modification of epigenetic marks. Further examination of these mechanisms may lead to earlier prevention and novel therapy for CVD.

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Conflict of interest statement

Competing interests: The authors declare no competing interests.

Figures

Figure 1

Epigenetics and atherosclerosis. Epigenetic changes, such as methylation and deacetylation, are associated with atherosclerosis and have been identified in specific tissues in the arterial wall; however, causal relationships have not been established. Enzymatic regulators of epigenetic processes, such as HDAC inhibitors, inhibit atherosclerosis. Altered methylation patterns occur in conjunction with SMC proliferation, which is suppressed by the HDAC inhibitor TSA. HDAC inhibitors also reduce monocyte adhesion to the endothelium. Abnormal DNA methylation is associated with plasma homocysteine levels, and methylation also regulates eNOS expression. HDAC inhibitors reduce angiogenesis through VEGF signaling in endothelial cells. in vulnerable plaques, DNA and the 15-lipoxygenase promoter are hypomethylated. Abbreviations: AdoHcy, adenosylhomocysteine; Dicer, endoribonuclease Dicer; Dnmt1, DNA (cytosine-5)-methyltransferase 1; EC, endothelial cell; eNOS, endothelial nitric oxide synthase; ER, estrogen receptor; HDAC, histone deacetylase; p21WAF1, leucine carboxyl methyltransferase 1; SMC, smooth muscle cell; TSA, trichostatin A; VCAM, vascular cell adhesion molecule; VEGF, vascular endothelial growth factor. Reprinted from Biochim. Biophys. Acta 1790(9), Turunen, M. P., Aavik, E. & Ylä-Herttuala, S. Epigenetics and atherosclerosis. 886–891 © 2009, with permission from Elsevier.

Figure 2

Epigenetic modifications that regulate transcription or translation. a. CpG dinucleotides are methylated by METs at the 5′ position of the cytosine residue. MBDs bind to methylated CpG DNA and repress transcription. Histone deacetylation also results in transcription repression. PcGs bind to the DNA and block access of transcription factors to DNA. in addition, they interact with HDACs and/or METs to mediate gene silencing, and contribute to histone methylation. Conversely, HATs and methyltransferases catalyze histone acetylation and methylation, which increases accessibility to DNA and gene activation. b. in the nucleus, miRNAs are transcribed by RNA polymerase ii to generate pri-miRNAs. These transcripts are processed by the Drosha/DGCR8 complex, which results in the formation of pre-miRNAs. Exportin 5 transports the pre-miRNAs into the cytoplasm, where Dicer processes them into ∼22-nucleotide duplexes that contain the mature miRNA duplex. Single-stranded miRNA is catalyzed through the activity of a helicase and binds to RISC, which directs the miRNA to target mRNAs. Two situations may occur: if the miRNA and target are complementary, translational degradation occurs; alternatively, if the complementarity is partial, then translation repression takes place. Abbreviations: DGCR8, microprocessor complex subunit DGCR8; Dicer, endoribonuclease Dicer; HAT, histone acetyltransferase; HDAC, histone deacetyltransferase; MBD, methyl CpG-binding protein; MET, methyltransferase; miRNA, microRNA; nt, nucleotide; PcG, polycomb group; pol II, polymerase II; pri-miRNA, primary transcripts; RiSC, RNA-induced silencing complex; TRBP, TAR RNA-binding protein.

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Epigenetics and cardiovascular disease - PubMed (original) (raw)