Manganese (II) induces chemical hypoxia by inhibiting HIF-prolyl hydroxylase: implication in manganese-induced pulmonary inflammation.
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-1alpha protein disappearance, which occurred by inhibiting HIF-prolyl hydroxylase (HPH), the key enzyme for HIF-1alpha hydroxylation and subsequent von Hippel-Lindau(VHL)-dependent HIF-1alpha degradation. HPH inhibition by manganese (II) was neutralized significantly by elevated dose of iron. Consistent with this, the induction of cellular HIF-1alpha 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.
Han
Jeongoh
J
Laboratory of Biomedicinal Chemistry, College of Pharmacy, Pusan National University, Busan 609-735, Republic of Korea.
Lee
Jong-Suk
JS
Choi
Daekyu
D
Lee
Youna
Y
Hong
Sungchae
S
Choi
Jungyun
J
Han
Songyi
S
Ko
Yujin
Y
Kim
Jung-Ae
JA
Kim
Young Mi
YM
Jung
Yunjin
Y
D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002712:Chlorides / Q000633:toxicity*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018836:Inflammation Mediators / Q000633:toxicity*; D017895:Manganese Compounds; D011014:Pneumonia / Q000139:chemically induced* / Q000201:enzymology* / Q000473:pathology; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D002712:Chlorides; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018836:Inflammation Mediators; D017895:Manganese Compounds; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D011393:Procollagen-Proline Dioxygenase; C025340:manganese chloride