Hypoxia-induced apoptosis of cementoblasts (OCCM-30) may be harmful to orthodontic treatment. Hypoxia-inducible factor 1-alpha (HIF-1α) 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-1α, 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-1α expression was inhibited despite the presence of three adipokines. Using dominant-negative mutants of HIF-1α, we found that siHIF-1α negatively regulated the caspase-8, caspase-9 and caspase-3 gene expression. We concluded that HIF-1α 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-1α 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.

中文翻译：

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缺氧诱导因子 1-α 在缺氧诱导的成牙骨质细胞凋亡中充当 ERK1/2 和半胱天冬酶之间串扰的桥梁因子

缺氧诱导的成牙骨质细胞凋亡（OCCM-30）可能对正畸治疗有害。缺氧诱导因子 1-α (HIF-1α) 介导缺氧期间的生物学效应。关于能够抵抗成牙骨质细胞凋亡的存活机制知之甚少。我们旨在使用化学模拟缺氧和脂肪因子的体外模型研究 HIF-1α 的潜在作用，以及与 ERK1/2 的蛋白质-蛋白质相互作用。_{在这里，OCCM-30 在 CoCl 2}模拟缺氧下与抵抗素、内脂素或生长素释放肽共同刺激。体外研究表明，CoCl ₂- 诱导的缺氧触发半胱天冬酶的激活，导致成牙骨质细胞凋亡功能障碍。抵抗素、内脂素和生长素释放肽促进 OCCM-30 细胞中磷酸化的 ERK1/2 表达。此外，这些脂肪因子在不同程度上抑制了缺氧诱导的细胞凋亡。用 ERK 抑制剂 (FR180204) 预处理可以逆转这些影响。在用 FR180204 处理的细胞中，尽管存在三种脂肪因子，但 HIF-1α 的表达受到抑制。使用 HIF-1α 的显性失活突变体，我们发现 siHIF-1α 负调控caspase - 8、caspase - 9和caspase - 3 基因表达。我们得出结论，HIF-1α 在 ERK1/2 依赖性途径中长期缺氧诱导的细胞凋亡中充当桥梁因子。显示caspase - 3、caspase - 8和caspase - 9的基因表达受脂肪因子（抵抗素、内脂素和生长素释放肽）的不同调节。因此，我们的研究为 ERK1/2 和 HIF-1α 在暴露于 CoCl ₂模拟缺氧条件下的 OCCM-30 细胞凋亡反应中的作用提供了证据，为接受正畸治疗的肥胖患者的分子干预提供了潜在的新可能性。