Tumor Necrosis Factor-Alpha and the ERK Pathway Drive Chemerin Expression in Response to Hypoxia in Cultured Human Coronary Artery Endothelial Cells

Abstract

BackgroundChemerin, a novel adipokine, plays a role in the inflammation status of vascular endothelial cells. Hypoxia causes endothelial-cell proliferation, migration, and angiogenesis. This study was aimed at evaluating the protein and mRNA expression of chemerin after exposure of human coronary artery endothelial cells (HCAECs) to hypoxia.Methods and ResultsCultured HCAECs underwent hypoxia for different time points. Chemerin protein levels increased after 4 h of hypoxia at 2.5% O2, with a peak of expression of tumor necrosis factor-alpha (TNF-alpha) at 1 h. Both hypoxia and exogenously added TNF-alpha during normoxia stimulated chemerin expression, whereas an ERK inhibitor (PD98059), ERK small interfering RNA (siRNA), or an anti-TNF-alpha antibody attenuated the chemerin upregulation induced by hypoxia. A gel shift assay indicated that hypoxia induced an increase in DNA-protein binding between the chemerin promoter and transcription factor SP1. A luciferase assay confirmed an increase in transcriptional activity of SP1 on the chemerin promoter during hypoxia. Hypoxia significantly increased the tube formation and migration of HCAECs, whereas PD98059, the anti-TNF-alpha antibody, and chemerin siRNA each attenuated these effects.ConclusionHypoxia activates chemerin expression in cultured HCAECs. Hypoxia-induced chemerin expression is mediated by TNF-alpha and at least in part by the ERK pathway. Chemerin increases early processes of angiogenesis by HCAECs after hypoxic treatment.

Chemerin Induced byTreponema pallidumPredicted Membrane Protein Tp0965 Mediates Endothelial Dysfunction via Activating MAPK Signaling Pathway

“…However, chemerin had no effect of the phosphorylation of p-JNK. These results agreed with findings reported in recent studies [46]. Kaur et al .…”

Inhibition of chemerin/CMKLR1 axis in neuroblastoma cells reduces clonogenicity and cell viability in vitro and impairs tumor growth in vivo

“…Furthermore, chemerin stimulation induced MMP production and angiogenesis [ 37 ]. Recent work by Chua et al demonstrates that hypoxia promotes chemerin expression in human coronary artery endothelial cells as well as migration and tube formation, supporting previous findings on the role of chemerin in angiogenesis [ 49 ]. However, the function of the chemerin/CMKLR1 axis in malignancies is probably tumor specific as both tumor promoting and tumor suppressing roles have been reported [ 15 – 18 , 20 , 30 , 31 ].…”

Association of Circulating Chemerin With Subclinical Parameters of Atherosclerosis

“… 2 Existing preclinical and animal studies reveal that chemerin with its large functional scope might have various actions in the vascular system. 8 – 11 , 45 – 48 …”