Circulating miRNA profiles provide a biomarker for severity of stroke outcomes associated with age and sex in a rat model

Abstract

Small non-coding RNA [miRNA (microRNA)] found in the circulation have been used successfully as biomarkers and mechanistic targets for chronic and acute disease. The present study investigated the impact of age and sex on miRNA expression following ischaemic stroke in an animal model. Adult (6 month) and middle-aged (11–12 months) female and male rats were subject to MCAo (middle cerebral artery occlusion) using ET-1 (endothelin-1). Circulating miRNAs were analysed in blood samples at 2 and 5 days post-stroke, and brain miRNAs were analysed at 5 days post-stroke. Although stroke-associated infarction was observed in all groups, infarct volume and sensory-motor deficits were significantly reduced in adult females compared with middle-aged females, adult males or middle-aged males. At 2 days post-stroke, 21 circulating miRNAs were differentially regulated and PCA (principal component analysis) confirmed that most of the variance was due to age. At 5 days post-stroke, 78 circulating miRNAs exhibited significantly different regulation, and most of the variance was associated with sex. A small cohort (five) of miRNAs, miR-15a, miR-19b, miR-32 miR-136 and miR-199a-3p, were found to be highly expressed exclusively in adult females compared with middle-aged females, adult males and middle-aged males. Predicted gene targets for these five miRNAs analysed for KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways revealed that the top ten KEGG pathways were related to growth factor signalling, cell structure and PI3K (phosphoinositide 3-kinase)/Akt and mTOR (mammalian target of rapamycin) signalling. Overall, the pattern of circulating miRNA expression suggests an early influence of age in stroke pathology, with a later emergence of sex as a factor for stroke severity.

Non-coding RNAs and neuroprotection after acute CNS injuries

“…Stroke was shown to rapidly alter the miRNA expression profiles in blood in both rodents and humans (Sepramaniam et al, 2014; Selvamani et al, 2014; Liu et al, 2010; Tan et al, 2009; Jeyaseelan et al, 2008). In some studies, expression profiling of blood was conducted in parallel with brain (Liu et al, 2010; Jeyaseelan et al, 2008) and CSF (Sørensen et al, 2014) that showed overlapping patterns of miRNA levels between blood/brain and blood/CSF.…”

Sexually dimorphic effects of gestational endocrine-disrupting chemicals on microRNA expression in the developing rat hypothalamus

“…Sexual dimorphisms in microRNA expression have become an area of investigation for neurobiological disorders with biases in prevalence and nature, such as autism, schizophrenia, and stroke (70–72). Furthermore, an increase in EDC exposures is beginning to be linked to the rise in these multifactorial disorders (73–75).…”

The Diagnostic Value of Circulating Brain-specific MicroRNAs for Ischemic Stroke

“…In ischemic stroke, the destruction of blood brain barrier and brain tissue injury release miRNAs into circulating blood (23,(26)(27)(28). To a certain extent, the levels of circulating miRNAs, especially brain-specific or brain-enriched miRNAs, may reflect the severity of cerebral infarction (29,30). In this study, our results showed that the plasma levels of the selected brain-specific or enriched miRNAs (miR-107, miR-128b and miR-153) were significantly elevated in stroke patients and they positively correlated with the severity of cerebral ischemic injury, thus confirming the diagnostic value of such miRNAs in ischemic stroke.…”