Long non-coding RNAs act as novel therapeutic targets by regulating molecular networks associated with ischemic stroke

Abstract

Impaired blood supply to part of the brain results in an ischemic stroke leading to dysfunction of brain tissue. Several genetic and environmental factors can contribute to stroke. Age is one of the most important risk factors for ischemic stroke. An increased incidence of stroke related mortalities is associated with aging. The pathophysiological processes triggered by stroke, such as inflammation, apoptosis, angiogenesis, and post-stroke recovery, are well described. However, the molecular mechanisms underlying disease development remain to be studied in detail. The damage and recovery process triggered by stroke is coordinately regulated by genes involved in inflammation, immune response, and angiogenesis. The transcriptional dynamics of these key pathways determine the recovery of brain tissue from damage.The long intergenic non-coding RNAs are the key regulators of gene expression regulation. In the present study, we sought to uncover the potential lncRNAs associated with stroke and aging. In the comparison of young and old Middle cerebral artery occlusion models (MCAo) mouse models with the age-matched controls, we found an up-regulation of 27 and 89 lncRNAs in the young and old mice, respectively, after stroke induction. Similarly, we found down-regulation of 24 lncRNAs in the old mice. In our study, we also found an up-regulation of the host genes for the microRNAs miR142 and mir-675.The potential cis-targets of the up-regulated lncRNAs are related to blood vessel morphogenesis, vascular development, and the immune system. Among the cis-targets of down-regulated lncRNAs, we find enrichment of genes involved in membrane action potential and regulation of blood circulation. Importantly, the magnitude of the cellular and molecular response to stroke correlates with differential expression of lncRNAs and the target genes. In conclusion, we demonstrate the association of lncRNAs with pathophysiological processes during stroke, such as apoptosis, angiogenesis, inflammation, blood-brain barrier breakdown, and neurogenesis.