International Journal of Molecular Medical Science, 2024, Vol.14, No.2, 132-143 http://medscipublisher.com/index.php/ijmms 135 Overall, DNA methylation serves as a critical regulatory mechanism in HHD, influencing the expression of key genes involved in hypertension and cardiac remodeling. Understanding these methylation patterns can provide insights into the pathogenesis of HHD and identify potential biomarkers for early diagnosis and therapeutic targets. 3.2 Histone modifications Histone modifications are another crucial epigenetic mechanism that regulates gene expression by altering chromatin structure. These modifications include acetylation, methylation, phosphorylation, and ubiquitination of histone proteins, which can either activate or repress transcription depending on the specific modification and its location. In HHD, histone modifications have been shown to play significant roles in the regulation of genes involved in cardiac hypertrophy and fibrosis. For instance, increased histone acetylation at specific lysine residues of histone H3 and H4 has been associated with the activation of pro-hypertrophic and pro-fibrotic genes. This acetylation enhances the accessibility of transcription factors to the DNA, promoting gene expression that contributes to cardiac remodeling (Liu and Tang, 2019). Conversely, histone methylation at particular lysine residues can lead to gene repression. For example, trimethylation of histone H3 at lysine 27 (H3K27me3) is a repressive mark found at the promoters of anti-fibrotic genes in hypertensive hearts, leading to their downregulation and facilitating fibrosis (Friso et al., 2015). Additionally, demethylation of histone H3 at lysine 4 (H3K4me3) is associated with the suppression of genes that protect against cardiac hypertrophy. The dynamic nature of histone modifications makes them attractive targets for therapeutic intervention. Drugs that modulate histone acetylation and methylation, such as histone deacetylase inhibitors, are being explored for their potential to reverse pathological gene expression patterns in HHD (Arif et al., 2019). 3.3 Non-coding RNAs (ncRNAs) Non-coding RNAs, particularly microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), have emerged as important regulators of gene expression in hypertensive heart disease. These ncRNAs do not encode proteins but instead regulate gene expression at the transcriptional and post-transcriptional levels. MicroRNAs are small RNA molecules that bind to complementary sequences on target mRNAs, leading to their degradation or inhibition of translation. Several miRNAs have been implicated in the pathogenesis of HHD. For example, miR-21 is upregulated in hypertensive hearts and promotes fibrosis by targeting and downregulating the expression of anti-fibrotic genes. Similarly, miR-29 and miR-133 have been shown to regulate genes involved in cardiac hypertrophy and fibrosis, contributing to the pathological remodeling seen in HHD (Levy et al., 2017). Long non-coding RNAs, which are longer RNA molecules, also play significant roles in HHD. They can interact with chromatin-modifying complexes, transcription factors, and other ncRNAs to regulate gene expression. For instance, the lncRNA MALAT1 has been shown to modulate endothelial function and vascular inflammation, both of which are critical in the development of hypertension and cardiac remodeling (Das et al., 2020). The regulatory roles of ncRNAs in HHD highlight their potential as therapeutic targets. Modulating the expression or activity of specific miRNAs or lncRNAs could offer new strategies for treating hypertension and preventing its cardiac complications (Udali et al., 2013). 4 Identification of Epigenetic Biomarkers in HHD 4.1 Criteria for biomarker identification The identification of epigenetic biomarkers in hypertensive heart disease (HHD) is guided by several stringent criteria to ensure their clinical validity, reliability, and utility. First, specificity and sensitivity are crucial; biomarkers must accurately reflect the presence and severity of HHD, distinguishing it from other cardiovascular or unrelated diseases. High sensitivity ensures the detection of even subtle changes associated with early stages of
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