The interactions between miR-126, HIF-1α, and HMGB1 play a crucial role in regulating inflammation and angiogenesis in different physiological and pathological conditions. miR-126 plays a dominant role in regulating HMGB1 and its downstream proinflammatory effectors in endothelial cells under hypoxia with concurrent acidosis, while HIF-1α expression is suppressed independently of miR-126 in these conditions. The findings suggest that the inflammatory responses of endothelial cells to hypoxia with acidosis are dynamically regulated by the interactions between hypoxia signaling, miR-126, and HIF-1α on the master regulator HMGB1.
Crosstalk between molecular regulators miR-126, hypoxia-inducible factor 1-alpha (HIF-1-alpha), and high-mobility group box-1 (HMGB1) contributes to the regulation of inflammation and angiogenesis in multiple physiological and pathophysiological settings. Here, we present evidence of an overriding role for miR-126 in the regulation of HMGB1 and its downstream proinflammatory effectors in endothelial cells subjected to hypoxia with concurrent acidosis (H/A). Methods. Primary mouse endothelial cells (PMEC) were exposed to hypoxia or H/A to simulate short or chronic low-flow ischemia, respectively. RT-qPCR quantified mRNA transcripts, and proteins were measured by western blot. ROS were quantified by fluorogenic ELISA and luciferase reporter assays employed to confirm an active miR-126 target in the HMGB1 3 ' UTR. Results. Enhanced expression of miR-126 in PMECs cultured under neutral hypoxia was suppressed under H/A, whereas the HMGB1 expression increased sequentially under both conditions. Enhanced expression of HMGB1 and downstream inflammation markers was blocked by the premiR-126 overexpression and optimized by antagomiR. Compared with neutral hypoxia, H/A suppressed the HIF-1 alpha expression independently of miR-126. The results show that HMGB1 and downstream effectors are optimally induced by H/A relative to neutral hypoxia via crosstalk between hypoxia signaling, miR-126, and HIF-1 alpha, whereas B-cell lymphoma 2(Bcl2), a HIF-1 alpha, and miR-126 regulated gene expressed optimally under neutral hypoxia. Conclusion. Inflammatory responses of ECs to H/A are dynamically regulated by the combined actions of hypoxia, miR-126, and HIF-1 alpha on the master regulator HMGB1. The findings may be relevant to vascular diseases including atherosclerotic occlusion and interiors of plaque where coexisting hypoxia and acidosis promote inflammation as a defining etiology.
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