miR-376b-5p regulates angiogenesis in cerebral ischemia

Abstract

Abstract. The profile of microRNAs (miRNAs) altered following middle cerebral artery occlusion (MCAO) and miRNAs are involved in angiogenesis following cerebral ischemia. miR-376b-5p was decreased following MCAO, however, whether miR-376b-5p is important in angiogenesis remains to be elucidated. The present study was designed to identify whether miR-376b-5p is involved in angiogenesis following cerebral ischemia and to elucidate the underlying mechanisms. A rat MCAO model was established and quantitative polymerase chain reaction was performed to analyze the mRNA expression level of miR-376b-5p for 1 to 7 days. In addition, the density of microvessels and the relative mRNA and protein levels of hypoxia-inducible factor-1 α (HIF-1α), vascular endothelial growth factor A (VEGFA) and Notch1 were measured. The miR-376b-5p mimic or the miR-376b-5p inhibitor were transfected into hypoxic human umbilical vein endothelial cells (HUVECs), and the proliferation, migration and tube formation were measured. To further examine the underlying mechanisms, shRNA was transfected into cells to knock down HIF-1α, and angiogenesis and the expression of associated molecules, including HIF-1α, VEGFA and Notch1 were compared between each group. Our results demonstrated that miR-376b-5p repressed angiogenesis in vivo and in vitro, and miR-376b-5p inhibited angiogenesis in HUVECs by targeting the HIF-1α-mediated VEGFA/Notch1 signaling pathway. These findings provide new insights into angiogenesis therapy for cerebral ischemia. IntroductionStroke is a life-threatening disease with a high incidence, high disability and high mortality rate, causing heavy economic burden to society and families. Cerebral infarction accounts for 80% of the total number of strokes (1). In the pathophysiological process of cerebral infarction, the recovery of the peripheral blood supply is an important factor for nerve cell prognosis (2). The clinical treatments for cerebral infarction, include thrombolysis, anticoagulation, blood pressure regulation and microcirculation improvement. The improvement and increase of blood supply in ischemic brain tissue, particularly in the ischemic penumbra, thereby improving energy metabolism of ischemic brain cells and saving neurons is one of the fundamental purposes and fundamental approaches for the treatment of cerebral ischemia.In recent years, a series of studies have revealed that good collateral circulation is able to reduce the infarct volume and reduce the risk of cerebral infarction recurrence (3,4). Clinical studies have provided preliminary evidence that promoting collateral circulation is able to lead to an improved clinical prognosis (5). Cerebral collateral circulation is blood flow which arrives in the ischemic area through other vessels (collateral or the newly formed vascular anastomosis) when arteries in the brain suffer severe stenosis or occlusion. Therefore, angiogenesis, as an effective method to improve the blood supply to the brain, is key for improving the prognosis of patients with stroke, and has...

Non-coding RNAs and neuroprotection after acute CNS injuries

“…1). A similar study indicated the role of miR-376b-5p in regulating the HIF-1α-mediated vascular endothelial growth factor (VEGF)/Notch1 signaling pathway following permanent MCAO in rats (Li et al, 2014a) (Fig. 1).…”

miR‐376b‐3p attenuates mitochondrial fission and cardiac hypertrophy by targeting mitochondrial fission factor

“…miR‐376b plays major roles in regulating of various biology activities including cancer, liver regeneration, angiogenesis and cardioprotection . Although no reports revealed the roles of miR‐376b in cardiac diseases, the present study showed miR‐376b‐3p participates in regulation cardiac hypertrophy by inhibiting mitochondrial fission in NRVCs.…”

Down‐regulation of miRNAs in the brain and development of diet‐induced obesity

“…Of note, there were no differences in the expression levels of miR ‐ 376b , which is a microRNA associated with various physiological processes including inflammation, (An et al, 2017; Li et al, 2014; Lu et al, 2015) across any brain region, suggesting that the observed reductions in miR‐155 and miR‐146a are not a consequence of a non‐specific reduction in miRNA biogenesis (Fig. 1).…”