Hypoxia-Inducible Factor 1-Alpha Acts As A Bridge Factor For Crosstalk Between Erk1/2 And Caspases In Hypoxia-Induced Apoptosis Of Cementoblasts
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE(2021)
摘要
Hypoxia-induced apoptosis of cementoblasts (OCCM-30) may be harmful to orthodontic treatment. Hypoxia-inducible factor 1-alpha (HIF-1 alpha) mediates the biological effects during hypoxia. Little is known about the survival mechanism capable to counteract cementoblast apoptosis. We aimed to investigate the potential roles of HIF-1 alpha, as well as the protein-protein interactions with ERK1/2, using an in-vitro model of chemical-mimicked hypoxia and adipokines. Here, OCCM-30 were co-stimulated with resistin, visfatin or ghrelin under CoCl2-mimicked hypoxia. In-vitro investigations revealed that CoCl2-induced hypoxia triggered activation of caspases, resulting in apoptosis dysfunction in cementoblasts. Resistin, visfatin and ghrelin promoted the phosphorylated ERK1/2 expression in OCCM-30 cells. Furthermore, these adipokines inhibited hypoxia-induced apoptosis at different degrees. These effects were reversed by pre-treatment with ERK inhibitor (FR180204). In cells treated with FR180204, HIF-1 alpha expression was inhibited despite the presence of three adipokines. Using dominant-negative mutants of HIF-1 alpha, we found that siHIF-1 alpha negatively regulated the caspase-8, caspase-9 and caspase-3 gene expression. We concluded that HIF-1 alpha acts as a bridge factor in lengthy hypoxia-induced apoptosis in an ERK1/2-dependent pathway. Gene expressions of the caspases-3, caspase-8 and caspase-9 were shown to be differentially regulated by adipokines (resistin, visfatin and ghrelin). Our study, therefore, provides evidence for the role of ERK1/2 and HIF-1 alpha in the apoptotic response of OCCM-30 cells exposed to CoCl2-mimicked hypoxia, providing potential new possibilities for molecular intervention in obese patients undergoing orthodontic treatment.
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关键词
adipokines, apoptosis, cementoblasts, cobalt (II) chloride, hypoxia
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