Manganese (II) induces chemical hypoxia by inhibiting HIF-prolyl hydroxylase: Implication in manganese-induced pulmonary inflammation |
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Authors: | Jeongoh Han Daekyu Choi Sungchae Hong Songyi Han Jung-Ae Kim Yunjin Jung |
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Institution: | a Laboratory of Biomedicinal Chemistry, College of Pharmacy, Pusan National University, Busan, 609-735, Republic of Korea b Medicinal Chemistry, College of Pharmacy, Pusan National University, Busan, Republic of Korea c Laboratory of Physiology, College of Pharmacy, Yeungnam University, Gyeongsan, Republic of Korea |
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Abstract: | Manganese (II), a transition metal, causes pulmonary inflammation upon environmental or occupational inhalation in excess. We investigated a potential molecular mechanism underlying manganese-induced pulmonary inflammation. Manganese (II) delayed HIF-1α protein disappearance, which occurred by inhibiting HIF-prolyl hydroxylase (HPH), the key enzyme for HIF-1α hydroxylation and subsequent von Hippel-Lindau(VHL)-dependent HIF-1α degradation. HPH inhibition by manganese (II) was neutralized significantly by elevated dose of iron. Consistent with this, the induction of cellular HIF-1α protein by manganese (II) was abolished by pretreatment with iron. Manganese (II) induced the HIF-1 target gene involved in pulmonary inflammation, vascular endothelial growth factor (VEGF), in lung carcinoma cell lines. The induction of VEGF was dependent on HIF-1. Manganese-induced VEGF promoted tube formation of HUVEC. Taken together, these data suggest that HIF-1 may be a potential mediator of manganese-induced pulmonary inflammation. |
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Keywords: | Manganese Hypoxia inducible factor Pulmonary inflammation HIF prolyl hydroxylase Vascular endothelial growth factor |
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