Circulation research, 2012-05, Vol.110 (11), p.1484-1497
2012
Details
- Autor(en) / Beteiligte
- Titel
- Dynamin-Related Protein 1–Mediated Mitochondrial Mitotic Fission Permits Hyperproliferation of Vascular Smooth Muscle Cells and Offers a Novel Therapeutic Target in Pulmonary Hypertension
- Ist Teil von
- Circulation research, 2012-05, Vol.110 (11), p.1484-1497
- Ort / Verlag
- Hagerstown, MD: American Heart Association, Inc
- Erscheinungsjahr
- 2012
- Link zum Volltext
- Quelle
- Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0009-7330eISSN: 1524-4571DOI: 10.1161/CIRCRESAHA.111.263848Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3539779
- Format
- –
- Schlagworte
- Animals, Antihypertensive Agents - pharmacology, Biological and medical sciences, Case-Control Studies, CDC2 Protein Kinase - metabolism, Cell Cycle Checkpoints, Cell Proliferation - drug effects, Cells, Cultured, Cobalt, Cyclin B1 - metabolism, Disease Models, Animal, Dynamins - genetics, Dynamins - metabolism, Enzyme Activation, Familial Primary Pulmonary Hypertension, Fundamental and applied biological sciences. Psychology, Genetic Therapy - methods, Glycolysis, GTP Phosphohydrolases - genetics, GTP Phosphohydrolases - metabolism, Humans, Hypertension, Pulmonary - enzymology, Hypertension, Pulmonary - etiology, Hypertension, Pulmonary - pathology, Hypertension, Pulmonary - therapy, Hypoxia - complications, Hypoxia-Inducible Factor 1, alpha Subunit - metabolism, Male, Medical sciences, Microtubule-Associated Proteins - genetics, Microtubule-Associated Proteins - metabolism, Mitochondria, Muscle - drug effects, Mitochondria, Muscle - enzymology, Mitochondria, Muscle - pathology, Mitochondrial Proteins - genetics, Mitochondrial Proteins - metabolism, Mitosis - drug effects, Monocrotaline, Muscle, Smooth, Vascular - drug effects, Muscle, Smooth, Vascular - enzymology, Muscle, Smooth, Vascular - pathology, Myocytes, Smooth Muscle - drug effects, Myocytes, Smooth Muscle - enzymology, Myocytes, Smooth Muscle - pathology, Phosphorylation, Pneumology, Pulmonary Artery - enzymology, Pulmonary Artery - pathology, Pulmonary hypertension. Acute cor pulmonale. Pulmonary embolism. Pulmonary vascular diseases, Quinazolinones - pharmacology, Rats, Rats, Sprague-Dawley, RNA Interference, Serine, Time Factors, Transfection, Vertebrates: cardiovascular system