MiR-451 protects against ischemic stroke by targeting Phd3

Abstract

Ischemic stroke still remains a therapeutic challenge due to its complex pathogenesis and implications. By screening biomarkers in the peripheral blood of ischemic stroke patients, miR-451 was identified as a differentially expressed miRNA along the disease course of ischemic stroke. To investigate the role of miR-451, middle cerebral artery occlusion (MCAO) was performed as an ischemic stroke model in mice. Intracerebroventricular administration of miR-451 mimic in the MCAO mice significantly decreased infarct size, while miR-451 inhibitor significantly increased infarct size. To understand the molecular mechanism of the protective effect of miR-451, Phd3 (also Egln3) was validated as a new miR-451 target. Either fewer or more Phd3-positive cells were observed in brain sections from mice receiving miR-451 mimic or inhibitor, respectively. In addition, the levels of p53 (a known Phd3 target) were significantly downregulated when the levels of Phd3 were reduced, suggesting its participation in reducing apoptosis after the miR-451 administration. Indeed, reduced apoptosis upon miR-451 mimic administration was detected by TUNEL staining. In conclusion, this study demonstrated a new protective role of miR-451 in cerebral ischemia and identified Phd3 as a novel miR-451 target, linking the mechanism to the involvement of p53 in the regulation of apoptosis during the pathogenesis of ischemic stroke.