Abstract
Previous studies have shown that the JAK2/STAT3 signaling pathway plays a regulatory role in cellular oxidative stress injury (OSI). In this study, we explored the role of the JAK2/STAT3 signaling pathway in hydrogen peroxide (H2O2)-induced OSI and the protective effect of melatonin against (H2O2)-induced injury in human umbilical vein endothelial cells (HUVECs). AG490 (a specific inhibitor of the JAK2/STAT3 signaling pathway) and JAK2 siRNA were used to manipulate JAK2/STAT3 activity, and the results showed that AG490 and JAK2 siRNA inhibited OSI and the levels of p-JAK2 and p-STAT3. HUVECs were then subjected to H2O2 in the absence or presence of melatonin, the main secretory product of the pineal gland. Melatonin conferred a protective effect against H2O2, which was evidenced by improvements in cell viability, adhesive ability and migratory ability, decreases in the apoptotic index and reactive oxygen species (ROS) production and several biochemical parameters in HUVECs. Immunofluorescence and Western blotting showed that H2O2 treatment increased the levels of p-JAK2, p-STAT3, Cytochrome c, Bax and Caspase3 and decreased the levels of Bcl2, whereas melatonin treatment partially reversed these effects. We, for the first time, demonstrate that the inhibition of the JAK2/STAT3 signaling pathway results in a protective effect against endothelial OSI. The protective effects of melatonin against OSI, at least partially, depend upon JAK2/STAT3 inhibition.
Highlights
Endothelial cells are crucial for maintaining the physiological functions of the cardiovascular system [1]
The results are expressed as the mean 6 standard error of the mean (SEM), n = 6, **P,0.01 compared to the control group, ##P,0.01 compared to the H2O2 group, $$P,0.01 compared to the H2O2+ AG (20 mM) group
Dong Y and colleagues provided the first evidence that cucurbitacin E (CuE) inhibited tumor angiogenesis by inhibiting the vascular endothelial growth factor receptor 2 (VEGFR2)-mediated JAK2/STAT3 and mitogen-activated protein kinase (MAPK) signaling pathways, and CuE might be a potential candidate in angiogenesis-related disease therapy [35]
Summary
Endothelial cells are crucial for maintaining the physiological functions of the cardiovascular system [1]. Increasing evidence suggests that oxidative stress in endothelial cells, as characterized by an imbalanced cellular capability to produce and eliminate reactive oxygen species (ROS), is involved in the pathophysiology of several vascular diseases, such as atherosclerosis, diabetes and hypertension [2]. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway is the signaling target of such proinflammatory cytokines as IL-6, which plays an important role in OSI [6]. JAK2/STAT3 signaling affects cellular activities, such as proliferation, migration, growth, differentiation and death [9]. Many studies have confirmed that the JAK2/STAT3 signal pathway is hyper-activated in cellular and animal models of OSI, suggesting an important role of this signaling pathway in regulating oxidative stress responses [10,11]. The modulation of the JAK2/STAT3 signaling pathway may provide an effective therapeutic strategy in the treatment of OSI
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