Dysregulation of Principal Circulating miRNAs in Non-human Primates Following Ischemic Stroke

Maybe early diagnosis of stroke but can't tell how fast it can be done or how difficult.

Dysregulation of Principal Circulating miRNAs in Non-human Primates Following Ischemic Stroke

Jian Chen^1†, Haiping Zhao^2†, Yuyou Huang², Yuqian Li², Junfen Fan², Rongliang Wang², Ziping Han², Zhenhong Yang², Longfei Wu¹, Di Wu², Yumin Luo^3* and Xunming Ji^3*

• ¹Department of Neurosurgery, Institute of Cerebrovascular Diseases Research, Xuanwu Hospital, Capital Medical University, Beijing, China
• ²National Clinical Research Center for Geriatric Disorders, Beijing, China
• ³Beijing Institute for Brain Disorders, Beijing, China

Despite the recent interest in plasma microRNA (miRNA) biomarkers in acute ischemic stroke patients, there is limited knowledge about the miRNAs directly related to stroke itself due to the multiple complications in patients, which has hindered the research progress of biomarkers and therapeutic targets of ischemic stroke. Therefore, in this study, we compared the differentially expressed miRNA profiles in the plasma of three rhesus monkeys pre- and post-cerebral ischemia. After cerebral ischemia, Rfam sequence category revealed increased ribosomic RNA (rRNA) and decreased transfer RNAs (tRNAs) in plasma. Of the 2049 miRNAs detected after cerebral ischemia, 36 were upregulated, and 76 were downregulated (fold change ≥2.0, P < 0.05). For example, mml-miR-191-5p, miR-421, miR-409-5p, and let-7g-5p were found to be significantly overexpressed, whereas mml-miR-128a-5p_R − 2, miR-431_R − 1, and let-7g-3p_1ss22CT were significantly downregulated. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses revealed that these differentially expressed miRNAs were implicated in the regulation of ubiquitin-mediated proteolysis and signaling pathways in cancer, glioma, chronic myeloid leukemia, and chemokine signaling. miRNA clustering analysis showed that mml-let-7g-5p and let-7g-3p_1ss22CT, which share three target genes [RB1-inducible coiled-coil 1 (RB1CC1), G-protein subunit γ 5 (GNG5), and chemokine (C-X-C motif) receptor 4 (CXCR4)], belong to one cluster, were altered in opposite directions following ischemia. These data suggest that circulating mml-let-7g may serve as a therapeutic target for ischemic stroke.

Introduction

Circulating microRNAs (miRNAs) might be useful as surrogate biomarkers for the diagnosis or prognosis of pathological conditions such as acute stroke; finding early blood miRNA biomarkers to diagnose this disease, for instance, could drastically reduce treatment delays. In addition, emerging RNA therapeutics targeting mRNAs have already been approved by the Food and Drug Administration for clinical research (Erdos et al., 2021) and have gained attention in cerebrovascular research. For example, RNA-targeted therapies to lower Lipoprotein(a) are in clinical development. Currently, there are approximately 7680 patients with a history of myocardial infarction, ischemic stroke, and symptomatic peripheral arterial disease (Tsimikas et al., 2021); this number helps estimate the potential therapeutic relevance of miRNAs for the treatment of ischemic stroke.

Ischemic stroke is a complex disease with several risk factors. Despite the increasing focus on plasma miRNA biomarkers in acute ischemic stroke patients (Singh et al., 2021), there is limited knowledge about the differentially expressed miRNAs directly related to stroke itself, which has hindered biomarker development and the definition of therapeutic targets. In this study, we compared the differences in circulating miRNAs in non-human primates, namely rhesus monkeys, before and after cerebral ischemia to identify the miRNAs directly related to ischemic stroke. The results of this research could help bridge the gap between in vivo rodent models and human patients, leading to therapeutic applications and valuable and accurate information for early detection of ischemic stroke.

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