Novel Role for the Regulation of Mitochondrial Fission by Hypoxia Inducible Factor-1α in the Control of Smooth Muscle Remodeling and Progression of Pulmonary Hypertension
2012; Lippincott Williams & Wilkins; Volume: 110; Issue: 11 Linguagem: Inglês
10.1161/circresaha.112.270801
ISSN1524-4571
Autores Tópico(s)ATP Synthase and ATPases Research
ResumoHomeCirculation ResearchVol. 110, No. 11Novel Role for the Regulation of Mitochondrial Fission by Hypoxia Inducible Factor-1α in the Control of Smooth Muscle Remodeling and Progression of Pulmonary Hypertension Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBNovel Role for the Regulation of Mitochondrial Fission by Hypoxia Inducible Factor-1α in the Control of Smooth Muscle Remodeling and Progression of Pulmonary Hypertension Michael S. Wolin Michael S. WolinMichael S. Wolin From the Department of Physiology and Pulmonary Hypertension Center, New York Medical College, Valhalla, NY. Originally published25 May 2012https://doi.org/10.1161/CIRCRESAHA.112.270801Circulation Research. 2012;110:1395–1397In this issue of Circulation Research, Marsboom et al1 describe a novel involvement of a mitochondrial fission regulatory pathway that is likely to be of great importance in pulmonary arterial hypertension (PAH)-associated smooth muscle remodeling. Data in the study provide evidence that this process appears to be controlled by activation of hypoxia inducible factor-1α (HIF-1α). As illustrated in the model in Figure, the stabilization or activation of HIF-1α in PAH is shown to promote mitochondrial fission by cyclin B1/CDK1-dependent phosphorylation of dynamin-related protein-1 (DRP1) at serine-616. The CDK1-cyclin B-dependent regulation of tubular mitochondria fragmentation by DRP1 was identified in previous studies as a regulator of the even distribution of mitochondria during mitosis in HeLa cells.2 Data in the study of Marsboom et al1 document how this process appears to be essential for the in vitro proliferation of pulmonary arterial smooth muscle cells from human hypertensive patients. In addition, evidence is provided for these mechanisms appearing to be a prominent contributing factor to pulmonary arterial remodeling in several different models of PAH.Download figureDownload PowerPointFigure. Model showing how conditions associated with pulmonary hypertension development promote hypoxia inducible factor (HIF)-1α regulation of pulmonary arterial smooth proliferative remodeling that appears to be controlled by a cyclin B1/CDK1-mediated phosphorylation of dynamin-related protein-1 (DRP1), which causes mitochondrial fission needed for their even distribution of during mitosis. The model also highlights approaches described in the text that were used to elucidate mechanisms.Article, see p 1484As described in the article of Marsboom et al,1 PAH is disorder in which small pulmonary arteries are obstructed, constricted, and inflamed in a manner that increases pulmonary vascular resistance, and this promotes right ventricular hypertrophy and eventually failure. Previous work from Archer et al identified many components of processes that evolved into the current new mechanism. For example, their studies provided evidence that an activation of HIF-1α under aerobic conditions in PAH was associated with a shifting from aerobic mitochondrial energy metabolism to a cancer cell–type emphasis on using aerobic glycolysis and mitochondrial fragmentation.3 Interestingly, promoting aerobic mitochondrial energy metabolism with the pyruvate dehydrogenase kinase inhibitor dichloroacetate has substantial protective effects against PAH associated with restoring a hypoxic sensing mechanism associated with mitochondrial-derived peroxide regulating voltage-gated potassium (Kv1.5) channels and decreasing HIF-1α activation.3 Dichloroacetate also prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis.4 These previous observations suggest shifting to aerobic glycolysis–associated energy metabolism is potentially an important factor in promoting the remodeling-associated pulmonary arterial smooth muscle proliferation.The article of Marsboom et al1 provides an extensive amount of impressive data to support the novel concepts in this article. Properties of this regulatory system were studied in lung tissue and pulmonary arterial smooth muscle cells from humans with PAH for comparison with pulmonary arterial smooth muscle cells from nonhypertensive controls. In addition, rat monocrotaline and chronic hypoxia models were studied, and a new model of pulmonary hypertension was developed based on cobalt chloride inducing HIF-1α in rats and pulmonary arterial smooth muscle cells. Human pulmonary arterial smooth muscle cells studies indicated that HIF-1α promoted a cyclin B1/CDK1-dependent phosphorylation of DRP1 at serine-616 in the mechanism of mitochondrial fission regulation using inhibitors of HIF-1α (chetomin) and DRP1 (Mdivi-1 and RO-3306). The PAH pulmonary arterial smooth muscle cells had elevated levels of HIF-1α under aerobic conditions, and studies with Mdiv-1 and siRNA for DRP1 resulted in evidence that cell-cycle arrest occurred in the G2/M phase. The impact of PAH conditions influencing mitochondrial fusion in pulmonary arterial smooth muscle cells was visualized in a movie showing the time-dependent spreading of a mitochondrial matrix fluorescent protein (Online Supplement). These cells also have properties suggesting there was a shift toward the use of aerobic glycolysis for energy metabolism in PAH. Activating HIF with CoCl2 or desferrioxamine or both promoted DRP1 serine-616 phosphorylation and rapid mitochondrial fragmentation in a manner attenuated by HIF-1α siRNA and Mdiv-1. Treatment of pulmonary arterial smooth muscle cells with CoCl2 was also shown to cause a shift in ion channel regulation associated with a reduction in Kv channels, depolarization, and increased intracellular calcium that are similar to changes seen in PAH. The mitochondrial fragmentation mechanism appears to be an active process in the remodeling observed in lung tissue from idiopathic PAH patients based on detection by imaging of elevated levels of HIF-1α, increased nuclear localization of cyclin B1, and increased serine-616 phosphorylation of DRP1 in pulmonary blood vessels with an external diameter <150 μm that have undergone pulmonary arterial smooth muscle cells proliferation or "muscularization." A chronic treatment of rats with CoCl2 for 4 weeks was observed to cause PAH associated with a reduction in mitochondrial size. The DRP1 inhibitor Mdivi-1 prevented the development of PAH in both this CoCl2 model and in a chronic hypoxia (4 weeks of 10% oxygen) rat model of PAH. Mdivi-1 also seemed to reverse indicators of hypertension when the therapy was started after 3 weeks in the rat monocrotaline model of PAH. Thus, data are provided showing the importance of the HIF-1α mitochondrial fission regulatory pathway across multiple animal and human models of PAH.Recent studies provide evidence that mitochondrial dynamics associated with proteins promoting fission and fusion are regulated by signaling mechanisms associated with adaptive physiological and pathophysiological processes.5 In the current study,1 the expression of mRNA for mitochondrial fusion protein mitofusin-2 (MFN2) was decreased, whereas mitochondrial fusion proteins mitofusin-1 (MFN1) and optic atrophy-1 were not different when pulmonary arterial smooth muscle cells from humans with PAH were compared with cells from control humans who were not hypertensive. In contrast, the profusion protein MFN2 was decreased in human PAH pulmonary arterial smooth muscle cells under conditions in which increased phosphorylation on serine-616 of the fission protein DRP1 was observed. Interestingly, it was observed in the present study that inhibition of DRP1 with Mdivi-1 reversed the fragmented phenotype and increased the MFN2. Increased MFN2 previously has been associated with promoting apoptosis in vascular smooth muscle cells.6 Recent studies in mice having conditional cardiac-specific ablation of MFN1 or MFN2 or both have provided insight into the metabolic and functional impact of mitochondrial fission promoted as a result of these proteins.7–9 The cardiac MFN1 deficiency results in small spherical mitochondria; however, the mice show rather normal cardiac and mitochondrial respiratory function.7 A cardiac MFN2 deficiency was actually associated with enlarged spherical mitochondria and some cardiac and mitochondrial respiratory dysfunction.8 Interestingly, both of these deficiencies were associated with a resistance to oxidant exposure promoting a mitochondrial transition pore response. In contrast, a combined ablation of cardiac myocyte MFN1 and MFN2 and its associated mitochondrial fragmentation resulted in mitochondrial respiratory dysfunction and rapid progression into a fatal dilated cardiomyopathy.9 Thus, mitochondrial fission and fusion are not specifically linked to a disruption of mitochondrial energy metabolism or highly energy-dependent processes like cardiac function. However, activation of DRP-1 and perhaps decreased MFN2 appear to contribute to promoting proliferative remodeling of vascular smooth muscle.The HIF-1α–controlled mitochondrial fission regulatory pathway illustrated in the Figure, which is reported in the article by Marsboom et al1 in the current issue of Circulation Research, is likely to be of great importance in physiological and pathophysiological processes involving vascular smooth muscle remodeling. Hypoxia sensing and oxidant mechanisms regulating HIF-1α10 provide pathways for its regulation by many types of stress-type conditions existing in vivo. Regulation of mitochondrial fission and other processes such as promoting aerobic glycolysis3,4 appear to enable the progression through mitosis that is needed for the stem cell–associated remodeling seen in pulmonary hypertension. Interestingly, Archer et al also recently have reported11 the 18F-fluorodeoxyglucose positron emission tomography tracer diagnostic method for imaging the enhanced glycolytic metabolism and its therapeutic reversal by dichloroacetate associated with controlling the hyperproliferative changes seen in small pulmonary arteries in PAH. Thus, the DRP1-regulated mechanism controlling mitochondrial fusion and proliferation described in the current issue of Circulation Research1 opens a new metabolism-associated target for therapies to treat pulmonary hypertension and perhaps other vascular remodeling-associated disease processes.Non-standard Abbreviations and Acronyms CDK1cyclin-dependent kinase 1DRP1dynamin-related protein-1HIF-1αhypoxia-inducible factor-1αKvvoltage-gated K+ channelMdivi-1mitochondrial division inhibitor-1MFN1mitofusin-1MFN2mitofusin-2PAHpulmonary arterial hypertensionPASMCpulmonary artery smooth muscle cellSources of FundingThe author's laboratory has been funded by National Institute of Health grants HL031069, HL043023, and HL066331.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Michael S. Wolin, PhD, Department of Physiology, Basic Sciences Building, Rm 604, New York Medical College, Valhalla, NY 10595. E-mail [email protected]eduReferences1. Marsboom G, Toth PT, Ryan JJ, et al. Dynamin-related protein 1-mediated mitochondrial mitotic fission permits hyperproliferation of vascular smooth muscle cells and offers a novel therapeutic target in pulmonary hypertension. Circ Res. 2012; 110:1484–1497.LinkGoogle Scholar2. Taguchi N, Ishihara N, Jofuku A, Oka T, Mihara K. Mitotic phosphorylation of dynamin-related GTPase Drp1 participates in mitochondrial fission. J Biol Chem. 2007; 282:11521–11529.CrossrefMedlineGoogle Scholar3. Bonnet S, Michelakis ED, Porter CJ, Andrade-Navarro MA, Thebaud B, Haromy A, Harry G, Moudgil R, McMurtry MS, Weir EK, Archer SL. An abnormal mitochondrial-hypoxia inducible factor-1alpha-Kv channel pathway disrupts oxygen sensing and triggers pulmonary arterial hypertension in fawn hooded rats: Similarities to human pulmonary arterial hypertension. 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May 25, 2012Vol 110, Issue 11 Advertisement Article InformationMetrics © 2012 American Heart Association, Inc.https://doi.org/10.1161/CIRCRESAHA.112.270801PMID: 22628570 Originally publishedMay 25, 2012 Keywordsdifferentiationsmooth muscle proliferationenergy metabolismpulmonary circulationdiseasePDF download Advertisement SubjectsMetabolismSmooth Muscle Proliferation and Differentiation
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