Abstract
Acute ischemic stroke (AIS) is a major public health problem in China. Impaired angiogenesis plays crucial roles in the development of ischemic cerebral injury. Recent studies have identified that microRNAs (miRNAs) are important regulators of angiogenesis, but little is known the exact effects of angiogenesis-associated miRNAs in AIS. In the present study, we detected the expression levels of angiogenesis-associated miRNAs in AIS patients, middle cerebral artery occlusion (MCAO) rats, and oxygen-glucose deprivation/reoxygenation (OGD/R) human umbilical vein endothelial cells (HUVECs). MiR-191 was increased in the plasma of AIS patients, OGD/R HUVECs, and the plasma and brain of MCAO rats. Over-expression of miR-191 promoted apoptosis, but reduced the proliferation, migration, tube-forming and spheroid sprouting activity in HUVECs OGD/R model. Mechanically, vascular endothelial zinc finger 1 (VEZF1) was identified as the direct target of miR-191, and could be regulated by miR-191 at post-translational level. In vivo studies applying miR-191 antagomir demonstrated that inhibition of miR-191 reduced infarction volume in MCAO rats. In conclusion, our data reveal a novel role of miR-191 in promoting ischemic brain injury through inhibiting angiogenesis via targeting VEZF1. Therefore, miR-191 may serve as a biomarker or a therapeutic target for AIS.
Highlights
Acute ischemic stroke (AIS) is a major cerebrovascular disease ascribing to the sudden reduction of cerebral blood flow, characterized by a series of cellular and molecular disturbances
We showed that up-regulation of miR-191 increased the apoptosis rate of Human Umbilical Vein Endothelial Cell (HUVEC) (Figure 3A, 3C), while down-regulation of miR-191 ameliorated the apoptosis induced by oxygen-glucose deprivation/reoxygenation (OGD/R) (Figure 3B, 3D)
We found that miR-191 overwww.aging-us.com expression significantly suppressed the mRNA levels of endothelin 1 (EDN1), MMP1, and stathmin 1 (STMN1) and but increased the mRNA level of CITED2 (Figure 7A, 7C, 7E, 7G)
Summary
Acute ischemic stroke (AIS) is a major cerebrovascular disease ascribing to the sudden reduction of cerebral blood flow, characterized by a series of cellular and molecular disturbances. Angiogenesis is the physiological process through which new blood vessels form by the extension or elaboration of existing vessels [7]. This process depending on endothelial cells is under the control of an extensive variety of angiogenic stimulators and inhibitors [8]. A growing number of studies have shown that microRNAs (miRNAs) are involved in the regulation of angiogenesis in ischemic diseases, including AIS [9,10,11]
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