1. Chronic Hypoxia-Induced Microvessel Proliferation and Basal Membrane Degradation in the Bone Marrow of Rats Regulated through the IL-6/JAK2/STAT3/MMP-9 Pathway.
- Author
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Zhu, Mingming, Yang, Min, Yang, Quanyu, Liu, Wenling, Geng, Hui, Pan, Li, Wang, Lu, Ge, Rili, Ji, Linhua, Cui, Sen, and Li, Zhanquan
- Subjects
ANIMAL experimentation ,HYPOXEMIA ,BLOOD vessels ,BONE marrow ,CELLULAR signal transduction ,DIMETHYL sulfoxide ,ELECTRON microscopy ,ENZYME inhibitors ,ENZYME-linked immunosorbent assay ,FLUORESCENT antibody technique ,GENE expression ,INTERLEUKINS ,BASAL lamina ,PHOSPHORYLATION ,POLYMERASE chain reaction ,RATS ,STAINS & staining (Microscopy) ,WESTERN immunoblotting ,REVERSE transcriptase polymerase chain reaction ,STAT proteins ,MATRIX metalloproteinases ,PATHOLOGIC neovascularization ,JANUS kinases ,DISEASE complications ,PHARMACODYNAMICS - Abstract
Chronic hypoxia (CH) is characterized by long-term hypoxia that is associated with microvessel proliferation and basal membrane (BM) degradation in tissues. The IL-6/JAK2/STAT3/MMP-9 pathway has been described in a variety of human cancers and plays an essential role in microvessel proliferation and BM degradation. Therefore, this study investigated the role of the IL-6/JAK2/STAT3/MMP-9 pathway in hypoxia-mediated microvessel proliferation and BM degradation in the rat bone marrow. Eighty pathogen-free Sprague Dawley male rats were randomly divided into four groups (20 per group)—control group, CH group (exposed to hypoxia in a hypobaric chamber at a simulated altitude of 5000 m for 28 d), CH + STAT3 inhibitor group (7.5 mg/kg/d), and CH + DMSO group. Microvessel density (MVD) and BM degradation in the bone marrow were determined by immunofluorescence staining and transmission electron microscopy. Serum IL-6 levels were assessed by enzyme-linked immunosorbent assay (ELISA), and the levels of P-JAK2, P-STAT3, and MMP-9 were assessed by western blot analysis and real-time reverse transcription PCR (RT-PCR). Hypoxia increased serum IL-6 levels, which in turn increased JAK2 and STAT3 phosphorylation, which subsequently upregulated MMP-9. Overexpression of MMP-9 significantly promoted the elevation of MVD and BM degradation. Inhibition of STAT3 using an inhibitor, SH-4-54, significantly downregulated MMP-9 expression and decreased MVD and BM degradation. Surprisingly, STAT3 inhibition also decreased serum IL-6 levels and JAK2 phosphorylation. Our results suggest that the IL-6/JAK2/STAT3/MMP-9 pathway might be related to CH-induced microvessel proliferation and BM degradation in the bone marrow. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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