title: Prolyl hydroxylase 3 interacts with Bcl-2 to regulate doxorubicin-induced apoptosis in H9c2 cells.
abstract: Prolyl hydroxylases (PHDs) are dioxygenases that use oxygen as a co-substrate to hydroxylate proline residues. Three PHD isoforms (PHD1, PHD2 and PHD3) have been identified in mammalian cells. PHD3 expression is upregulated in some cardiac diseases such as cardiomyopathy, myocardial ischemia-reperfusion injury and congestive heart failure, all of which are associated with apoptosis. However, the role of PHDs in cardiomyocyte apoptosis remains unknown. Here, we have found that exposure of embryonic rat heart-derived H9c2 cells to doxorubicin (DOX) induced cell apoptosis as evaluated by caspase-3/7 activity, mitochondrial membrane potential (Δψm) and cell viability, and that this apoptosis was linked to PHD3 upregulation. PHD inhibition or PHD3 silencing substantially ameliorated DOX-induced apoptosis, but PHD1 or PHD2 knockdown did not significantly influence apoptosis. Furthermore, immunoprecipitation experiments showed that PHD3 upregulation reduced the formation of the Bax-Bcl-2 complex, inhibiting the anti-apoptotic effect of Bcl-2. Thus, PHD3 upregulation may be partially responsible for DOX-induced cardiomyocyte apoptosis via its interaction with Bcl-2. Inhibition of PHD3 is likely to be cardioprotective against apoptosis in some heart disorders.
authors.affiliation: Key Laboratory of Arrhythmias, Ministry of Education, East Hospital, Tongji University School of Medicine, 200120 Shanghai, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.forename: Zhaoxia
authors.initials: Z
authors.lastname: Huo
authors.forename: Biao
authors.initials: B
authors.lastname: Yan
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Lin
authors.forename: Zhao-Nian
authors.initials: ZN
authors.lastname: Zhou
authors.forename: Xingqun
authors.initials: X
authors.lastname: Liang
authors.forename: Weidong
authors.initials: W
authors.lastname: Zhu
authors.forename: Dandan
authors.initials: D
authors.lastname: Liang
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.forename: Hong
authors.initials: H
authors.lastname: Zhao
authors.forename: Yunfu
authors.initials: Y
authors.lastname: Sun
authors.forename: Yi-Han
authors.initials: YH
authors.lastname: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D004317:Doxorubicin / Q000494:pharmacology; D006801:Humans; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D011393:Procollagen-Proline Dioxygenase / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D051381:Rats
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D004317:Doxorubicin; D011393:Procollagen-Proline Dioxygenase; C030606:proline, 2-oxoglutarate 3-dioxygenase