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Myocardial hypoxia-induced endothelial cell apoptosis contributes to cardiac dysfunction, such as myocardial infarction (MI), myocardial ischemia, and heart failure. Thus, it is important to investigate the molecular mechanisms of vascular endothelial cells (VECs) during exposure to hypoxia. SP-1 is an important regulator of cytokines associated with cell functions. We found that SP-1 expression increased in human umbilical vein endothelial cells (HUVECs) exposed to hypoxia by western blot. Then the SP-1 siRNA was transfected into HUVECs under hypoxic condition. MTT assay showed that hypoxia reduced the cell proliferation, but SP-1 siRNA reversed that. Transfection with si-SP-1 also reversed cell apoptosis and reactive oxygen species (ROS) production increased by hypoxia treatment. Moreover, inflammatory phenotype were increased in hypoxia induced HUVECs, including ICAM-1,VCAM-1 levels as well as TNFα, IL-6 and IL-1β secretion, and the si-SP-1 also reversed this effect of hypoxia. Additionally, si-SP-1 increased expression of miR-135b and reduced expression of hypoxia-inducible factor 1-α (HIF-1α), which is the target gene of miR-135b. To investigate the underlying mechanism of SP-1 on hypoxia induced HUVECs injury, the anti-miR-135b or HIF-1α agonist (CoCl2) were used. Finally, the result indicated that both anti-miR-135b or CoCl2 treatment reversed the effects of SP-1 siRNA under hypoxia. In conclusion, the SP-1/miR-135b/HIF-1α axis may play a critical role in hypoxia-induced vascular endothelial injury. Our study thus provides novel insights into the role of this transcription factor and miRNAs in the pathogenesis of hypoxia-induced cardiac dysfunctions.Expression of SP-1 and miR-135b in hypoxia-exposed HUVECs.SP-1 loss affected cell proliferation and apoptosis in HUVECs exposed to hypoxia.SP-1 loss attenuated hypoxia-induced levels of inflammatory factors and VEGF.SP-1 loss increased miR-135b and reduced HIF-1α expression in HUVECs.SP-1/miR-135b/HIF-1α was a novel axis in hypoxia-induced injury in HUVECs.