Epigenetics of Atherosclerosis

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EPIGENETICS OF ATHEROSCLEROSIS Murugan Veerapandian 2010-50065 Advanced Genetics 28-May-2010

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Background Information Atherosclerosis (arteriosclerotic vascular disease or ASVD) Definition: Atherosclerosis is a chronic disease of large and medium sized arteries which is characterized by accumulation of cholesterol in the arterial wall together with proliferation of arterial smooth muscle cells (SMC) and accumulation of extracellular matrix components which lead to occlusion of blood vessels, myocardial infarction, peripheral vascular disease, amputations, aneurysms and stroke

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Background Information Atherosclerosis (arteriosclerotic vascular disease or ASVD) Survey Ref: www.diseaseproof.com/archives/2008/03/

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Signs & Symptoms None Chest Pain Shortness Of Breath Heart Attack Signs and Symptoms Cause Factors Background Information

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Background Information

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Risk Factors Uncontrollable Sex Hereditary Race Age Controllable High blood pressure High blood cholesterol Smoking Physical activity Obesity Diabetes Stress and anger Background Information

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Screening and Diagnosis Background Information

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Treatment Stenting Angioplasty Bypass surgery Background Information

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Epigenetic View

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1. Hypercholesterolemia and potential dietary effects Hypercholesterolemia is central to the initial stages of atherosclerosis in large arteries Folate and methionine deficiency- biosynthesis of methyl donor S-adenosyl-methionine, can lead to altered imprinting of IGF2 Risk of colorectal cancer-dietary folate deficiency and MTHF reductase that direct folate to remethylation of homocysteine (Hcy) to methionine

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2. Homocysteinemia, epigenetics in atherosclerosis Hyperhomocysteinemia-elevated plasma Hcy= ischemic heart disease and stroke Patients with vascular disease have disturbed global DNA methylation status associated with increased plasma Hcy and Adenosyl-Hcy concentrations High blood Hcy levels (>75 μmol/l) correlate with DNA hypomethylation and atherosclerosis Lipid metabolism Transport Or via oxidative stress and endoplasmic reticulum stress Elevated Hcy decreases the bioavailability of NO 135 genes regulates the blood levels of Hcy JAMA 288 (2002) 2015.

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3. DNA Methylation and Atherosclerosis Biochim. Biophy. Acta 1790 (2009) 886–891

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3.1 Hypermethylation Some promoters like iNOS and FGF2 are hypermethylated Increased methylation of ERα promoter has been detected in atheromas as well as in the phenotypic switch from quiescent SMCs to a proliferative state ERβ promoter shows a high level of methylation in cells from the plaque area compared to non-plaque regions Age-related promoter hypermethylation of c-myc, c-fos, IGF2, MYOD1, N33, HIC1, versican, PAX6, DBCCR1, E-cadherin and P15 has been reported Inflammation promotes hypermethylation of peripheral blood lymphocyte DNA and Inflammation in dialysis patients correlate CV mortality Biochim. Biophy. Acta 1790 (2009) 886–891

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3.2 Hypomethylation Ageing Observed in 9% of SMC proliferation in advanced human atherosclerotic plaques Similar hypomethylation- atheromas of ApoE (Apolipoprotein E) knock out mice Neointimal thickenings of New Zealand White rabbit aortas Hypomethylation of eNOS and iNOS promoter areas are characteristic of healthy human vascular endothelial cells Featured by reduction in the methylation status of extracellular SOD and 15-Lipoxygenase promoters are characteristic of atherosclerotic lesions Associate-autoantibody against oxidized LDL Biochim. Biophy. Acta 1790 (2009) 886–891

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Ref: Biochimica et Biophysica Acta 1790 (2009) 886–891

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4. Histone code and Atherosclerosis Histone demethylases- gene expression, cellular differentiation and development Dysregulation of epigenetic histone modifications may be a major underlying mechanism for metabolic memory and sustained proinflammatory phenotype in SMCs in diabetic vascular disease SMCs derived from a mouse model of type 2 diabetes displayed enhanced inflammatory gene expression and proatherogenic responses Histone code modifications -chronic vascular inflammation, and metabolic memory associated with diabetic vascular complications Epigenetic chromatin histone modifications and gene expression

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Summary of potential epigenetic effects in atherosclerosis and vascular wall

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when CpG dinucleotides in the gene promoter are unmethylated, transcription factors and rNA Polymerase can bind to their specific nucleotide sequences and transcription of coding sequences (exons) occurs Methylation of CpGs by DNA methyltransferases leads to the binding of methyl-CpG binding protein 2, which in turn recruits the histone modifying enzymes histone deacetylase and histone methyltransferase to form a complex that is bound to the promoter This complex deacetylates histones and catalyzes methylation of specific lysine residues These modifications cause the chromatin strand to adopt a ‘tight’ conformation, which prevents access of transcription factors and rNA polymerases to the DNA and results in the silencing of transcription Abbreviations: HDAC, histone deacetylase; HMT, histone methyltransferase; MeCP2, methyl-CpG binding protein 2; P, promoter; Pol, rNA polymerase; TF, transcription factor Epigenetic modulation of gene expression Ref: Nat. Rev. Endocrinol. 5, 401–408 (2009)

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Environmental Sensitivity of the Epigenome throughout life Ref: Nat. Rev. Endocrinol. 5, 401–408 (2009)

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Ref: Marín-García: Cardiac epigenetic and gene therapy Gene Therapy for CVD

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Gene Therapy for CVD

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Thank you