Dynamin-related protein 1-mediated mitochondrial mitotic fission permits hyperproliferation of vascular smooth muscle cells and offers a novel therapeutic target in pulmonary hypertension

Glenn Marsboom, Peter T. Toth, John J. Ryan, Zhigang Hong, Xichen Wu, Yong Hu Fang, Thenappan Thenappan, Lin Piao, Hannah J. Zhang, Jennifer Pogoriler, Yimei Chen, Erik Morrow, E. Kenneth Weir, Jalees Rehman, Stephen L. Archer

Research output: Contribution to journalArticlepeer-review

286 Scopus citations

Abstract

Rationale: Pulmonary arterial hypertension (PAH) is a lethal syndrome characterized by pulmonary vascular obstruction caused, in part, by pulmonary artery smooth muscle cell (PASMC) hyperproliferation. Mitochondrial fragmentation and normoxic activation of hypoxia-inducible factor-1α (HIF-1α) have been observed in PAH PASMCs; however, their relationship and relevance to the development of PAH are unknown. Dynamin-related protein-1 (DRP1) is a GTPase that, when activated by kinases that phosphorylate serine 616, causes mitochondrial fission. It is, however, unknown whether mitochondrial fission is a prerequisite for proliferation. Objective: We hypothesize that DRP1 activation is responsible for increased mitochondrial fission in PAH PASMCs and that DRP1 inhibition may slow proliferation and have therapeutic potential. Methods and Results: Experiments were conducted using human control and PAH lungs (n=5) and PASMCs in culture. Parallel experiments were performed in rat lung sections and PASMCs and in rodent PAH models induced by the HIF-1α activator, cobalt, chronic hypoxia, and monocrotaline. HIF-1α activation in human PAH leads to mitochondrial fission by cyclin B1/CDK1-dependent phosphorylation of DRP1 at serine 616. In normal PASMCs, HIF-1α activation by CoCl2 or desferrioxamine causes DRP1-mediated fission. HIF-1α inhibition reduces DRP1 activation, prevents fission, and reduces PASMC proliferation. Both the DRP1 inhibitor Mdivi-1 and siDRP1 prevent mitotic fission and arrest PAH PASMCs at the G2/M interphase. Mdivi-1 is antiproliferative in human PAH PASMCs and in rodent models. Mdivi-1 improves exercise capacity, right ventricular function, and hemodynamics in experimental PAH. Conclusions: DRP-1-mediated mitotic fission is a cell-cycle checkpoint that can be therapeutically targeted in hyperproliferative disorders such as PAH.

Original languageEnglish (US)
Pages (from-to)1484-1497
Number of pages14
JournalCirculation research
Volume110
Issue number11
DOIs
StatePublished - May 25 2012
Externally publishedYes

Keywords

  • cyclin B1/cyclin-dependent kinase 1
  • hypoxia-inducible factor-1
  • mitochondrial division inhibitor-1
  • mitochondrial fission
  • mitotic checkpoint

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