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Cardiovascular and Epigenetics


Introduction of cardiovascular and epigenetics

Without changes in DNA sequences, epigenetics refers to changes in biological phenotypes and gene expression patterns, including DNA methylation, histone modifications, chromatin remodeling, non-coding RNA, etc. Epigenetics has 3 layers meaning: (1) heritable, that is, the changes can be inherited by cells or individual generations through mitosis or meiosis; (2) reversible gene expression regulation; (3) not accompanied the changes in DNA sequence or cannot be used sequence changes are explained, and genetic information is mainly preserved in the form of DNA methylation and histone post-translational modifications. Since epigenetic changes are reversible, this provides a new approach to the treatment of disease. The research on epigenetics is no longer limited to the field of genetics. The study found that epigenetics has far-reaching significance in the occurrence and prevention of major diseases such as cardiovascular diseases and tumors. In recent years, cardiovascular diseases, tumors, type-2 diabetes, and metabolic syndrome are considered to be important human diseases controlled by epigenetic. These diseases include the following important characteristics: (1) even in the same family or in the same genetic background, its incidence is also unpredictable, and does not completely follow the Mendelian inheritance law. There are differences in gender and genetic likelihood in their patient population. (2) Prenatal effects, including maternal diets, fetal malnutrition and overnutrition, and other changes in the prenatal environment, are important causes of disease in adulthood. (3) The risk of disease increases with age. It can be seen that epigenetics plays an important role in elucidating the interaction between genes and the environment and changing the course of disease. An in-depth study of the epigenetic mechanisms of cardiovascular disease is conducive to the development of effective defense strategies for cardiovascular disease, while the reversibility of epigenetic changes provides new opportunities for the intervention of diet and other environmental factors to intervene in cardiovascular disease.

Cardiovascular disease, also known as circulatory disease, is a series of diseases involving the circulatory system. The circulatory system refers to the organs and tissues that transport blood in the human body, including the heart and blood vessels (arteries, veins, and microvessels), which can be subdivided into acute and chronic, generally associated with arteriosclerosis. These diseases have similar causes, disease processes and treatments. Mainly include: hypertension, atherosclerosis, heart failure, arrhythmia, sudden death from sport, angina pectoris, acute myocardial infarction, coronary heart disease and hyperlipidemia. Cardiovascular disease is a common disease that seriously threatens human health, so it is necessary to study it.

Cardiovascular and Epigenetics

The relationship of cardiovascular and epigenetics

With the study of cardiovascular disease, researchers have found a close relationship between cardiovascular disease and epigenetics.

High blood pressure

As one of the candidate genes for essential hypertension, α-adduction gene has a lower methylation level of promoter, which increases the risk of essential hypertension. In clinical, the methylation level of promoter of α-adduction gene has significant gender differences. The methylation level of the CpG1 locus in the α-adduction promoter of female patients was significantly lower than that in the normal control group, but there was no significant difference in male patients compared with the normal control group. However, in male patients, the methylation level of CpG2-5 was lower than the normal control group, and the methylation level of the female patient was not different from the normal control group. Abnormal methylation of PPARγ and angiotensin-converting enzyme genes can affect the pathogenesis of hypertension. MiRNAs also play an important role in the pathogenesis of hypertension. MiRNA-130a regulates the proliferation of vascular smooth muscle cells. MiRNA-155 is involved in the regulation of the activity of the renin angiotensin aldosterone system by affecting the expression of angiotensin II receptors. MiRNA-17, 21, 145, 204, 208, etc. participate in the pathogenesis of hypertension through vascular endothelial injury, platelet damage, angiogenesis, cardiac hypertrophy and the like.

Atherosclerosis and coronary heart disease

Atherosclerosis refers to vascular changes that occur in the large and middle arteries, with atherosclerotic plaques as pathological features, and are the pathological basis of many diseases. A study of peripheral blood leukocyte genomic methylation suggests that genomic methylation levels are positively correlated with coronary heart disease incidence and exposure to coronary heart disease risk factors. Researchers found that the estrogen and androgen receptor gene, monocarboxylate transporter, p53, extracellular superoxide dismutase gene, tissue factor pathway inhibitor 2 genes, platelet growth factor A, etc. are atherosclerosis-related genes. Their abnormal methylation is associated with the development of atherosclerosis. Dong et al. found that the expression of miRNA-21 was significantly decreased in the myocardial infarction area, while the expression in the marginal area was significantly up-regulated. In addition, the expression of miRNA-1 and miRNA-26 was also significantly increased in the myocardial infarction model, suggesting that miRNA-1 and miRNA-26 may be involved in myocardial apoptosis induced by myocardial infarction.

Cardiac hypertrophy and cardiomyopathy

Studies have found that deacetylation is linked by HDACs to inhibit transcription, and rats lacking HDAC1 and HDAC2 show severe cardiac malformations and dilated cardiomyopathy. Overexpression of type I HDACs lead to increasing ventricular thickness, whereas the absence of HDAC3 in 4-month-old idiopathic heart disease results in severe cardiac hypertrophy. Divakaran et al. found that cardiac-specific miRNA-208 regulates cardiomyocyte hypertrophy and fibrosis.

In addition, some key transcription factors associated with cardiac gene expression in cardiomyocytes are defective, leading to congenital heart disease. Similarly, deletions of miRNAs can cause severe developmental malformations of heart. Interestingly, changes in blood flow during heart development also affect the formation of the heart by epigenetic manner. Previous studies have shown that endothelial cells (EC) cover the inner surface of blood vessels and are the interface between blood vessels and blood flow. The shear stress (SS) of the blood flow has an influence on the function and thrombosis of EC. Hemorheology can affect cardiac construction through epigenetic mechanisms, and insufficient SS can lead to ventricular and valvular malformations. SS regulates gene expression by triggering epigenetic modifications of histones and activating transcriptase-induced acetyltransferases, which in turn affects ESCs differentiation. SS can affect the acetylation of lysine H3 histone, phosphorylation of serine and methylation of lysine, and promote the transcription of the vascular endothelial growth factor receptor 2 (VEGFR2) promoter, resulting in the expression of cardiovascular specific proteins. It includes early expression of smooth muscle actin, smooth muscle protein 22-a, platelet-endothelial cell adhesion molecule-1, VEG-FR2 and the like.

Cardiovascular disease is an important disease that currently threatens human health. Targeted therapy by finding its molecular mechanism has become the focus of discipline research. According to the research, researchers found that epigenetics is closely related to cardiovascular diseases. Therefore, the feature of epigenetics can act as a new diagnosis and treatment tool for cardiovascular diseases, using its reversibility of modification can help to find effective intervention targets.

References:

  1. Zhang LN, et al. Lower ADD1 gene promoter DNA methylation increases the risk of essential hypertension. PLOS One. 2013, 8(5): e63455.
  2. Kim M, et al. DNA methylation as a biomarker for cardiovascular disease risk. PLOS One. 2010,5(3):e9692.
  3. Dong SM, et al. MiRNA expression signature and the role of miRNA-21 in the early phase of acute myoeardial infarction. ASBMB. 2009,284(43): 29514-29525.
  4. Shan ZX, et al. Upregulated expression of miR-1/miR-206 in a rat model of myocardial infarction. Biochem Biphys Res Commun. 2009, 381(4):597-601.
  5. Trivedi CM, et al. Transgenic overexpression of Hdac3 in the heart produces increased postnatal cardiac myocyte proliferation but does not induce hypertrophy. J Biol Chem. 2008, 283(38): 26484-9.
  6. Montgomery RL, et al. Maintenance of cardiac energy metabolism by histone deacetylase 3 in mice. J Clin Invest. 2008,118(11):3588-97.
  7. Divakaran V, Mann DL. The emerging role of miRNAs in cardiac remodeling and heart failure. Circ Res. 2008, 103(6):1072-1083.
  8. Vallaster M, et al. Epigenetic mechanisms in cardiac development and disease. Acta Biochim Biophys Sin. 2012, 44(1):92-102.

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