Synthetically designed circRNA can be used to target cardiovascular relevant microRNAs to improve cellular function.

Abstract

Vascular aging, endothelial dysfunction, and cellular senescence are interconnected processes that drive cardiovascular diseases (CVDs). Several studies have confirmed that microRNAs (miRNAs) are closely associated with the development of CVDs. Among them, miR-21-5p and miR-146a-5p have emerged as critical players in CVDs: MiR-21-5p is implicated in promoting inflammation and fibrosis, while miR-146a-5p influences vascular smooth muscle cell proliferation and inflammatory responses. Targeting these miRNAs for therapeutic intervention could provide a novel strategy to mitigate the deleterious effects of vascular aging. Recent advances in RNA-based therapeutics have led to the exploration of circular RNAs (circRNAs) as stable and effective miRNA inhibitors. Due to their circular structure, circRNAs exhibit greater stability than linear miRNA inhibitors, such as anti-miRs. This study aimed to evaluate the expression of miR-21-5p and miR-146a-5p in senescent human vascular endothelial cells and vascular smooth muscle cells (VSMCs) and to assess whether synthetic circRNAs could effectively inhibit these miRNAs. In a series of experiments, human umbilical vein endothelial cells (HUVECs) and VSMCs were transfected with custom-designed circRNAs targeting these miRNAs. Here, we want to focus on VSMCs. The effects on miRNA expression, target gene regulation, and cellular functions such as proliferation and migration were analyzed. Our findings demonstrate that circRNA-mediated inhibition of miR-21-5p and miR-146a-5p significantly affects gene expression and cellular behavior in senescent vascular cells, suggesting that circRNAs may serve as more efficient and stable therapeutic agents compared to traditional anti-miRs. By addressing these objectives, this study contributes to the growing body of knowledge on circRNA-mediated miRNA inhibition and its potential implications for vascular health. The results from this study not only enhance our understanding of miR-21-5p and miR-146a-5p in vascular senescence but also provide a foundation for future therapeutic strategies.