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.
Highlights
Chronic hypoxia (CH) is a condition where the partial pressure of oxygen in the blood is too low to saturate hemoglobin, which may be due to various reasons, including the decrease in the amount of breathable oxygen owing to a reduced barometric pressure [1], often encountered in pilots, mountain climbers, and people living at high altitudes
Characteristics of the Rat Model of Chronic Hypoxia. e CH rat model was established in the CH, CH + inhibitor, and CH + DMSO groups. e rats under CH showed typical symptoms, including cyanosis in the mucous membrane of the lips, tongue, ears, palms, and soles of feet compared to the control group
Our results suggest that CH significantly increased serum IL-6 which induced the increased phosphorylation of JAK2 and STAT3 resulting in the overexpression of MMP-9. ese results are in line with previous studies [18,19,20,21,22,23,24,25,26,27,28,29]
Summary
Chronic hypoxia (CH) is a condition where the partial pressure of oxygen in the blood is too low to saturate hemoglobin, which may be due to various reasons, including the decrease in the amount of breathable oxygen owing to a reduced barometric pressure [1], often encountered in pilots, mountain climbers, and people living at high altitudes. People inhabiting high altitudes are considered to be exposed to CH and show excessive erythrocytosis and hypoxemia [2, 3]. Previous studies showed that CH arises due to the excessive production of erythrocytes, which increases the blood viscosity causing blood flow retardation leading to exacerbated hypoxic-ischemic injury and eventually angiogenesis and basal membrane (BM) degradation of the blood vessel in tissues [6,7,8,9,10]. BioMed Research International study, we showed that patients with CH frequently exhibit an erythematic facial color with marked congestion of the mucosa and conjunctiva as a result of the formation of new vessels and that CH is associated with changes in bone marrow MVD [6]. The mechanisms underlying the development of CH-induced changes in the microvessels are relatively unknown
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