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Epigenetic Regulation by microRNAs in Hyperhomocysteinemia-Accelerated Atherosclerosis
Raquel Griñán1,2, Joan Carles Escolà-Gil1,3, Josep Julve1,3
1Institut d'Investigació Biomèdica Sant Pau (IIB SANT PAU), 08041 Barcelona, Spain.
Insights
High homocysteine (Hcy) levels accelerate atherosclerosis through poorly understood epigenetic mechanisms. MicroRNAs (miRNAs) are key epigenetic regulators implicated in this process and show promise as therapeutic targets for Hcy-induced cardiovascular disease.
Area of Science:
- Epigenetics and Molecular Biology
- Cardiovascular Disease Pathophysiology
- Biomarker Discovery
Background:
- Elevated serum homocysteine (Hcy) is a significant risk factor for cardiovascular diseases, particularly atherosclerosis.
- The exact molecular mechanisms linking Hcy to vascular disease progression are not fully elucidated.
- Epigenetic modifications, including DNA methylation, histone modification, and microRNA (miRNA) activity, play crucial roles in regulating gene expression during atherosclerosis development.
Purpose of the Study:
- To review and summarize the current understanding of microRNA involvement in hyperhomocysteinemia (HHcy)-mediated atherogenesis.
- To explore the potential of miRNAs as therapeutic targets for Hcy-induced atherosclerosis.
- To highlight the role of miRNAs as potential biomarkers for HHcy-related cardiovascular risk.
Main Methods:
- Comprehensive literature review of studies investigating miRNAs in the context of Hcy and atherosclerosis.
- Analysis of preclinical data on specific miRNA dysregulations (e.g., miR-143, miR-125b, miR-92, miR195-3p, miR-148a/152) in Hcy-accelerated vascular disease models.
- Examination of research on miRNA-based therapeutic strategies and biomarker potential.
Main Results:
- Downregulation of specific miRNAs (e.g., miR-143, miR-125b) affects vascular smooth muscle cell proliferation.
- Dysregulated miRNAs (e.g., miR-92, miR195-3p) influence foam cell cholesterol accumulation and macrophage inflammation in preclinical models.
- Reciprocal regulation between miRNAs (miR-148a/152) and DNA methyltransferase 1 (DNMT1) is observed in Hcy-accelerated atherosclerosis.
- Certain miRNAs (miR-143, miR-217) show potential as biomarkers for HHcy patients at risk of atherosclerosis.
Conclusions:
- MicroRNAs are critical epigenetic regulators implicated in the pathogenesis of Hcy-induced atherosclerosis.
- Specific miRNAs demonstrate potential as diagnostic biomarkers and therapeutic targets for managing Hcy-related cardiovascular complications.
- Further research into miRNA-based therapies is warranted to address Hcy-induced atherogenicity.
Abstract:
Increased serum levels of homocysteine (Hcy) is a risk factor for cardiovascular disease and is specifically linked to various diseases of the vasculature such as atherosclerosis. However, the precise mechanisms by which Hcy contributes to this condition remain elusive. During the development of atherosclerosis, epigenetic modifications influence gene expression. As such, epigenetic modifications are an adaptive response to endogenous and exogenous factors that lead to altered gene expression by methylation and acetylation reactions of different substrates and the action of noncoding RNA including microRNAs (miRNAs). Epigenetic remodeling modulates cell biology in both physiological and physiopathological conditions. DNA and histone modification have been identified to have a crucial role in the progression of atherosclerosis. However, the potential role of miRNAs in hyperHcy (HHcy)-related atherosclerosis disease remains poorly explored and might be essential as well. There is no review available yet summarizing the contribution of miRNAs to hyperhomocystein-mediated atherogenicity or their potential as therapeutic targets even though their important role has been described in numerous studies. Specifically, downregulation of miR-143 or miR-125b has been shown to regulate VSCMs proliferation in vitro. In preclinical studies, downregulation of miR-92 or miR195-3p has been shown to increase the accumulation of cholesterol in foam cells and increase macrophage inflammation and atherosclerotic plaque formation, respectively. Another preclinical study found that there is a reciprocal regulation between miR-148a/152 and DNMT1 in Hcy-accelerated atherosclerosis. Interestingly, a couple of studies have shown that miR-143 or miR-217 may be used as potential biomarkers in patients with HHcy that may develop atherosclerosis. Moreover, the current review will also update current knowledge on miRNA-based therapies, their challenges, and approaches to deal with Hcy-induced atherosclerosis.
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