Role of miR-181 Family Members in Stroke: Insights into Mechanisms and Therapeutic Potential

Abstract

Stroke is a major cause of mortality and long-term disability worldwide, making early diagnosis and effective treatment crucial for reducing its impact. In response to the limited efficacy of current treatments, alternative therapeutic strategies, such as novel biomarkers and therapies, are emerging to address this critical unmet medical need. MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression at the post-transcriptional level. Due to their dysregulation, they have been implicated in the onset and progression of various diseases. Recent research highlighted the important role of miR-181 family members in the context of stroke. Polymorphisms such as rs322931 in miR-181b are associated with increased stroke risk. miR-181 family members are aberrantly expressed and related to various aspects of stroke pathology, affecting inflammatory responses or neuronal survival. We provide a comprehensive overview of how alterations in miR-181 expression influence stroke mechanisms and their potential as therapeutic targets.

Keywords: biological processes; cerebral ischemia; miR-181 family members.

Figure 1

Genomic distribution and the secondary structures of the miR-181 family members across human chromosomes. (A) Location of miR-181 family members across three different human chromosomes. Chromosome 1 harbors the miR-181a1 and miR-181b1 transcript, depicted as adjacent segments on the DNA strand. Chromosome 9 contains the miR-181a2 and miR-181b2 transcripts, which are similar to those on chromosome 1. Chromosome 19 includes the miR-181c and miR-181d, positioned next to each other on the DNA strand. (B) Sequences for mature hsa-miR-181 family members were downloaded from miRBase (http://mirbase.org, 27 September 2024) and used as input to generate the secondary structures by RNA structure software [36].

Figure 2

Biological roles and implications of miR-181 family members in cellular processes, illustrating the diverse biological functions and implications of the miR-181 family across various cellular processes, particularly in the context of oxidative stress, neuroinflammation, cell proliferation and survival, cellular death, and angiogenesis. (A). Oxidative Stress. Upregulation of miR-181a leads to increased production of reactive oxygen species (ROS), contributing to oxidative stress within cells. (B). Neuroinflammation. miR-181a downregulates the expression of pro-inflammatory cytokines, reducing neuroinflammation. miR-181b acts to decrease neuroinflammation. miR-181c reduces levels of TNF-α, a key inflammatory cytokine. miR-181c targets HMGB1 and is regulated by Malat1, contributing to an anti-inflammatory effect. (C). Cell Proliferation and Survival. miR-181a inhibits the En2 gene and the Wnt/β-catenin pathway. Therefore, the downregulation of the miR can regulate cell proliferation and survival. (D). Cellular Death. miR-181a/d downregulates anti-apoptotic genes, leading to increased neuronal apoptosis. It also plays a role in maintaining cellular homeostasis and reducing inflammatory responses, which may influence cell survival. (E). Angiogenesis and Hypoxic Response. miR-181b modulates angiogenesis through PTEN/Akt signaling and HIF-1α-independent pathways, enhancing the function of endothelial cells and promoting the formation of new blood vessels. Figure created in BioRender.com.