Non-coding RNA and atherosclerosis

The human genome predominantly encodes RNA molecules that do not translate into proteins, known as non-coding RNAs (ncRNAs). These ncRNAs play pivotal roles in gene expression regulation and their dysregulation is linked to various diseases, including atherosclerosis. ncRNAs can be classified into housekeeping ncRNAs, such as ribosomal RNA (rRNA) and transfer RNA (tRNA), and regulatory ncRNAs, which include small non-coding RNAs (sncRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs). Among sncRNAs, microRNAs (miRNAs) and small interfering RNAs (siRNAs) are well-studied for their roles in gene regulation through interactions with messenger RNA (mRNA).

Mechanisms and Functions of ncRNAs

miRNAs, typically around 22 nucleotides long, regulate gene expression by binding to complementary sequences on target mRNAs, leading to mRNA cleavage, translation repression, or degradation of mRNA ends. The first identified miRNA, lin-4 from Caenorhabditis elegans, regulates larval development by repressing the translation of the lin-14 gene.

siRNAs share similarities with miRNAs but function through distinct mechanisms. They often arise from double-stranded RNA and mediate gene silencing by degrading target mRNA in a sequence-specific manner. Both miRNAs and siRNAs are crucial in maintaining cellular homeostasis and their dysregulation can contribute to pathological conditions.

lncRNAs, which are longer than 200 nucleotides, regulate gene expression at various levels, including chromatin modification, transcription, and post-transcriptional processing. They can act as molecular scaffolds, guides, decoys, or enhancers, influencing the expression of neighboring or distant genes. circRNAs, characterized by their covalently closed loop structures, act as miRNA sponges, interact with RNA-binding proteins, and even translate into functional peptides in some cases. These diverse functions of ncRNAs underscore their significance in cellular processes and disease mechanisms.

ncRNAs in Atherosclerosis

Atherosclerosis, characterized by the buildup of plaques within arterial walls, involves complex molecular mechanisms in which ncRNAs play significant roles. ncRNAs influence various stages of atherosclerosis, including lipid metabolism, inflammation, and vascular cell function. For instance, miRNAs are involved in the regulation of cholesterol efflux and foam cell formation, which are critical in plaque development.

Several miRNAs have been identified as key regulators in atherosclerosis. For example, miR-146a/b modulates inflammatory responses by targeting pro-inflammatory cytokines IL-6 and IL-8, while miR-21 promotes angiogenesis through the activation of AKT and ERK signaling pathways. The intricate balance of these miRNAs is crucial for vascular health and their dysregulation can exacerbate atherosclerotic processes.

lncRNAs also play critical roles in atherosclerosis. For example, lncRNA ANRIL is associated with increased risk of coronary artery disease by regulating the expression of genes involved in cell proliferation and apoptosis. Similarly, lncRNA MALAT1 has been shown to influence endothelial cell function and inflammatory response, contributing to plaque stability and vascular inflammation.

circRNAs, though less studied, are emerging as important regulators in atherosclerosis. circRNA_000203, for instance, has been implicated in the regulation of vascular smooth muscle cell proliferation and migration, processes essential for plaque formation and stability.

Therapeutic Potential of ncRNAs

Given their regulatory roles, ncRNAs represent promising therapeutic targets for atherosclerosis. Strategies to modulate ncRNA activity, such as miRNA mimics or inhibitors, have shown potential in preclinical studies. For instance, targeting miR-21 with specific inhibitors can reduce pathological angiogenesis and improve vascular function. Additionally, the delivery of ncRNAs or their modulators using nanoparticles or viral vectors offers a novel approach to treat atherosclerosis at the molecular level.

Therapeutic targeting of lncRNAs is also being explored. Antisense oligonucleotides (ASOs) can be designed to specifically bind and degrade lncRNAs, reducing their pathological effects. For example, ASOs targeting lncRNA ANRIL have been shown to reduce atherosclerotic lesion formation in animal models.

The development of circRNA-based therapies is still in its infancy, but the potential is significant. Synthetic circRNAs that act as miRNA sponges or that encode therapeutic peptides could provide new avenues for treatment.

Conclusions

ncRNAs are critical regulators of gene expression with significant roles in the pathogenesis of atherosclerosis. Understanding their mechanisms and functions provides insights into the molecular basis of this disease and opens new avenues for therapeutic interventions. Continued research into ncRNAs will likely lead to the development of innovative treatments aimed at mitigating the burden of atherosclerosis and improving cardiovascular health.

This essay outlines the essential roles and therapeutic potential of ncRNAs in atherosclerosis, emphasizing their regulatory functions and the promising strategies for targeting these molecules in disease treatment.

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https://www.xiahepublishing.com/1555-3884/GE-2023-00117

The study was recently published in the Gene Expression.

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