MicroRNA in ischemic stroke etiology and pathology

Abstract

Small, noncoding, microRNAs (miRNAs) have emerged as key mediators of posttranscriptional gene silencing in both pathogenic and pathological aspects of ischemic stroke biology. In stroke etiology, miRNA have distinct expression patterns that modulate pathogenic processes including atherosclerosis (miR-21, miR-126), hyperlipidemia (miR-33, miR-125a-5p), hypertension (miR-155), and plaque rupture (miR-222, miR-210). Following focal cerebral ischemia, significant changes in the miRNA transcriptome, independent of an effect on expression of miRNA machinery, implicate miRNA in the pathological cascade of events that include blood brain barrier disruption (miR-15a) and caspase mediated cell death signaling (miR-497). Early activation of miR-200 family members improves neural cell survival via prolyl hydroxylase mRNA silencing and subsequent HIF-1α stabilization. Pro- (miR-125b) and anti-inflammatory (miR-26a, -34a, -145, and let-7b) miRNA may also be manipulated to positively influence stroke outcomes. Recent examples of successfully implemented miRNA-therapeutics direct the future of gene therapy and offer new therapeutic strategies by regulating large sets of genes in related pathways of the ischemic stroke cascade.

Fig. 1.

Ischemic stroke etiology. A: a thrombotic stroke occurs when diseased or damaged cerebral arteries become blocked by the formation of atherosclerotic plaque within the brain. Clinically referred to as focal cerebral thrombosis or cerebral infarction, this classification of stroke is responsible for half of all clinically presented stroke cases. An embolic stroke is also caused by cerebrovascular occlusion of atherosclerotic plaque origin, but in this case the plaque (or emboli) ruptures from a distal site, travels in the blood, and occludes a distal point in the cerebrovascular system. B: biologically validated miRNA identified to play a role in ischemic stroke etiology.