Abstract
Pulmonary arterial hypertension (PAH) is characterized by a hyperproliferative and anti-apoptotic diathesis within the vascular wall of the resistance pulmonary arteries, leading to vascular lumen occlusion, right ventricular failure, and death. Most current therapies show poor efficacy due to emphasis on vasodilation (rather than proliferation/apoptosis) and a lack of specificity to the pulmonary circulation. The multiple molecular abnormalities described in PAH are diverse and seemingly unrelated, calling for therapies that attack comprehensive, integrative mechanisms. Similar abnormalities also occur in cancer where a cancer-specific metabolic switch toward a non-hypoxic glycolytic phenotype is thought to be not only a result of several primary molecular or genetic abnormalities but also underlie many aspects of its resistance to apoptosis. In this paper, we review the evidence and propose that a metabolic, mitochondria-based theory can be applied in PAH. A pulmonary artery smooth muscle cell mitochondrial remodeling could integrate a number of diverse molecular abnormalities described in PAH and respond by orchestrating a switch toward a cancer-like glycolytic phenotype that drives resistance to apoptosis; via redox and calcium signals, this mitochondrial remodeling may also regulate critical transcription factors like HIF-1 and nuclear factor of activated T cells that have been described to play an important role in PAH. Because mitochondria in pulmonary arteries are quite different from mitochondria in systemic arteries, they could form the basis of relatively selective PAH therapies. This metabolic theory of PAH could facilitate the development of novel diagnostic and selective therapeutic approaches in this disease that remains deadly.
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Weir EK, Lopez-Barneo J, Buckler KJ, Archer SL (2005) Acute oxygen-sensing mechanisms. N Engl J Med 353:2042–2055
Pan JG, Mak TW (2007) Metabolic targeting as an anticancer strategy: dawn of a new era? Sci STKE 2007:pe14
Michelakis ED, Webster L, Mackey JR (2008) Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer. Br J Cancer 99:989–994
Denko NC (2008) Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nat Rev Cancer 8:705–713
Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324:1029–1033
Michelakis ED (2006) Spatio-temporal diversity of apoptosis within the vascular wall in pulmonary arterial hypertension: heterogeneous BMP signaling may have therapeutic implications. Circ Res 98:172–175
Jurasz P, Courtman D, Babaie S, Stewart DJ (2010) Role of apoptosis in pulmonary hypertension: from experimental models to clinical trials. Pharmacol Ther 126:1–8
Tuder RM, Cool CD, Yeager M, Taraseviciene-Stewart L, Bull TM, Voelkel NF (2001) The pathobiology of pulmonary hypertension. Endothelium. Clin Chest Med 22:405–418
Archer SL, Michelakis ED (2006) An evidence-based approach to the management of pulmonary arterial hypertension. Curr Opin Cardiol 21:385–392
Humbert M, Morrell NW, Archer SL, Stenmark KR, MacLean MR, Lang IM, Christman BW, Weir EK, Eickelberg O, Voelkel NF et al (2004) Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol 43:13S–24S
Michelakis ED, Wilkins MR, Rabinovitch M (2008) Emerging concepts and translational priorities in pulmonary arterial hypertension. Circulation 118:1486–1495
Archer SL, Weir EK, Wilkins MR (2010) Basic science of pulmonary arterial hypertension for clinicians: new concepts and experimental therapies. Circulation 121:2045–2066
Newman JH, Wheeler L, Lane KB, Loyd E, Gaddipati R, Phillips JA 3rd, Loyd JE (2001) Mutation in the gene for bone morphogenetic protein receptor II as a cause of primary pulmonary hypertension in a large kindred. N Engl J Med 345:319–324
Remillard CV, Tigno DD, Platoshyn O, Burg ED, Brevnova EE, Conger D, Nicholson A, Rana BK, Channick RN, Rubin LJ et al (2007) Function of Kv1.5 channels and genetic variations of KCNA5 in patients with idiopathic pulmonary arterial hypertension. Am J Physiol Cell Physiol 292:C1837–C1853
Michelakis ED, Hampl V, Nsair A, Wu X, Harry G, Haromy A, Gurtu R, Archer SL (2002) Diversity in mitochondrial function explains differences in vascular oxygen sensing. Circ Res 90:1307–1315
Kim JW, Dang CV (2005) Multifaceted roles of glycolytic enzymes. Trends Biochem Sci 30:142–150
Wallace DC (2005) A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu Rev Genet 39:359–407
Zamzami N, Kroemer G (2001) The mitochondrion in apoptosis: how Pandora’s box opens. Nat Rev Mol Cell Biol 2:67–71
Halestrap A (2005) Biochemistry: a pore way to die. Nature 434:578–579
Archer SL, Michelakis ED, Thebaud B, Bonnet S, Moudgil R, Wu XC, Weir EK (2006) A central role for oxygen-sensitive K+ channels and mitochondria in the specialized oxygen-sensing system. Novartis Found Symp 272:157–171, discussion 171–155, 214–157
Remillard CV, Yuan JX (2004) Activation of K+ channels: an essential pathway in programmed cell death. Am J Physiol Lung Cell Mol Physiol 286:L49–L67
Platoshyn O, Golovina VA, Bailey CL, Limsuwan A, Krick S, Juhaszova M, Seiden JE, Rubin LJ, Yuan JX (2000) Sustained membrane depolarization and pulmonary artery smooth muscle cell proliferation. Am J Physiol Cell Physiol 279:C1540–C1549
Rizzuto R, Marchi S, Bonora M, Aguiari P, Bononi A, De Stefani D, Giorgi C, Leo S, Rimessi A, Siviero R et al (2009) Ca(2+) transfer from the ER to mitochondria: when, how and why. Biochim Biophys Acta 1787:1342–1351
Huang LE, Arany Z, Livingston DM, Bunn HF (1996) Activation of hypoxia-inducible transcription factor depends primarily upon redox-sensitive stabilization of its alpha subunit. J Biol Chem 271:32253–32259
MacKenzie ED, Selak MA, Tennant DA, Payne LJ, Crosby S, Frederiksen CM, Watson DG, Gottlieb E (2007) Cell-permeating alpha-ketoglutarate derivatives alleviate pseudohypoxia in succinate dehydrogenase-deficient cells. Mol Cell Biol 27:3282–3289
Thompson CB (2009) Metabolic enzymes as oncogenes or tumor suppressors. N Engl J Med 360:813–815
Crabtree GR, Olson EN (2002) NFAT signaling: choreographing the social lives of cells. Cell 109(Suppl):S67–S79
Bushdid PB, Osinska H, Waclaw RR, Molkentin JD, Yutzey KE (2003) NFATc3 and NFATc4 are required for cardiac development and mitochondrial function. Circ Res 92:1305–1313
Kim JW, Tchernyshyov I, Semenza GL, Dang CV (2006) HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab 3:177–185
Pastorino JG, Hoek JB, Shulga N (2005) Activation of glycogen synthase kinase 3beta disrupts the binding of hexokinase II to mitochondria by phosphorylating voltage-dependent anion channel and potentiates chemotherapy-induced cytotoxicity. Cancer Res 65:10545–10554
Pastorino JG, Hoek JB (2008) Regulation of hexokinase binding to VDAC. J Bioenerg Biomembr 40:171–182
McMurtry MS, Bonnet S, Wu X, Dyck JR, Haromy A, Hashimoto K, Michelakis ED (2004) Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis. Circ Res 95:830–840
Bonnet S, Michelakis ED, Porter CJ, Andrade-Navarro MA, Thebaud B, Haromy A, Harry G, Moudgil R, McMurtry MS, Weir EK et al (2006) 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. Circulation 113:2630–2641
Bonnet S, Rochefort G, Sutendra G, Archer SL, Haromy A, Webster L, Hashimoto K, Bonnet SN, Michelakis ED (2007) The nuclear factor of activated T cells in pulmonary arterial hypertension can be therapeutically targeted. Proc Natl Acad Sci USA 104:11418–11423
Dohi T, Beltrami E, Wall NR, Plescia J, Altieri DC (2004) Mitochondrial survivin inhibits apoptosis and promotes tumorigenesis. J Clin Invest 114:1117–1127
McMurtry MS, Archer SL, Altieri DC, Bonnet S, Haromy A, Harry G, Puttagunta L, Michelakis ED (2005) Gene therapy targeting survivin selectively induces pulmonary vascular apoptosis and reverses pulmonary arterial hypertension. J Clin Invest 115:1479–1491
Michelakis ED, Sutendra G, Dromparis P, Webster L, Haromy A, Niven E, Maguire C, Gammer TL, Mackey JR, Fulton D et al (2010) Metabolic modulation of glioblastoma with dichloroacetate. Sci Transl Med 2:31ra34
Bonnet S, Archer SL, Allalunis-Turner J, Haromy A, Beaulieu C, Thompson R, Lee CT, Lopaschuk GD, Puttagunta L, Harry G et al (2007) A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell 11:37–51
Quash G, Fournet G, Reichert U (2003) Anaplerotic reactions in tumour proliferation and apoptosis. Biochem Pharmacol 66:365–370
Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, Fantin VR, Jang HG, Jin S, Keenan MC et al (2009) Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462:739–744
Gatenby RA, Gillies RJ (2004) Why do cancers have high aerobic glycolysis? Nat Rev Cancer 4:891–899
Kim JW, Dang CV (2006) Cancer’s molecular sweet tooth and the Warburg effect. Cancer Res 66:8927–8930
Vousden KH, Ryan KM (2009) p53 and metabolism. Nat Rev Cancer 9:691–700
Matoba S, Kang JG, Patino WD, Wragg A, Boehm M, Gavrilova O, Hurley PJ, Bunz F, Hwang PM (2006) p53 regulates mitochondrial respiration. Science 312:1650–1653
Tomlinson IP, Alam NA, Rowan AJ, Barclay E, Jaeger EE, Kelsell D, Leigh I, Gorman P, Lamlum H, Rahman S et al (2002) Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet 30:406–410
Douwes Dekker PB, Hogendoorn PC, Kuipers-Dijkshoorn N, Prins FA, van Duinen SG, Taschner PE, van der Mey AG, Cornelisse CJ (2003) SDHD mutations in head and neck paragangliomas result in destabilization of complex II in the mitochondrial respiratory chain with loss of enzymatic activity and abnormal mitochondrial morphology. J Pathol 201:480–486
Lodish MB, Adams KT, Huynh TT, Prodanov T, Ling A, Chen C, Shusterman S, Jimenez C, Merino M, Hughes M et al (2009) Succinate dehydrogenase gene mutations are strongly associated with paraganglioma of the organ of Zuckerkandl. Endocr Relat Cancer 17:581–588
Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ et al (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360:765–773
Michelakis ED, McMurtry MS, Wu XC, Dyck JR, Moudgil R, Hopkins TA, Lopaschuk GD, Puttagunta L, Waite R, Archer SL (2002) Dichloroacetate, a metabolic modulator, prevents and reverses chronic hypoxic pulmonary hypertension in rats: role of increased expression and activity of voltage-gated potassium channels. Circulation 105:244–250
Guignabert C, Tu L, Izikki M, Dewachter L, Zadigue P, Humbert M, Adnot S, Fadel E, Eddahibi S (2009) Dichloroacetate treatment partially regresses established pulmonary hypertension in mice with SM22alpha-targeted overexpression of the serotonin transporter. FASEB J 23:4135–4147
Nemenoff RA, Simpson PA, Furgeson SB, Kaplan-Albuquerque N, Crossno J, Garl PJ, Cooper J, Weiser-Evans MC (2008) Targeted deletion of PTEN in smooth muscle cells results in vascular remodeling and recruitment of progenitor cells through induction of stromal cell-derived factor-1alpha. Circ Res 102:1036–1045
Sutendra G, Bonnet S, Rochefort G, Haromy A, Folmes KD, Lopaschuck GD, Dyck JRB, Michelakis ED (2010) Fatty acid oxidation and malonyl-CoA decarboxylase in vascular remodeling of pulmonary hypertension. Sci Transl Med 2:44ra58
Archer SL, Marsboom G, Kim GH, Zhang HJ, Toth PT, Svensson EC, Dyck JR, Gomberg-Maitland M, Thebaud B, Husain AN et al (2010) Epigenetic attenuation of mitochondrial superoxide dismutase 2 in pulmonary arterial hypertension. A basis for excessive cell proliferation and a new therapeutic target. Circulation 121:2661–2671
Zamanian RT, Hansmann G, Snook S, Lilienfeld D, Rappaport KM, Reaven GM, Rabinovitch M, Doyle RL (2009) Insulin resistance in pulmonary arterial hypertension. Eur Respir J 33:318–324
Rabinovitch M (2010) PPARgamma and the pathobiology of pulmonary arterial hypertension. Adv Exp Med Biol 661:447–458
Xu W, Koeck T, Lara AR, Neumann D, DiFilippo FP, Koo M, Janocha AJ, Masri FA, Arroliga AC, Jennings C et al (2007) Alterations of cellular bioenergetics in pulmonary artery endothelial cells. Proc Natl Acad Sci USA 104:1342–1347
Fijalkowska I, Xu W, Comhair SA, Janocha AJ, Mavrakis LA, Krishnamachary B, Zhen L, Mao T, Richter A, Erzurum SC et al (2010) Hypoxia inducible-factor1alpha regulates the metabolic shift of pulmonary hypertensive endothelial cells. Am J Pathol 176:1130–1138
Sehgal PB, Mukhopadhyay S (2007) Pulmonary arterial hypertension: a disease of tethers, SNAREs and SNAPs? Am J Physiol Heart Circ Physiol 293:H77–H85
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Dromparis, P., Sutendra, G. & Michelakis, E.D. The role of mitochondria in pulmonary vascular remodeling. J Mol Med 88, 1003–1010 (2010). https://doi.org/10.1007/s00109-010-0670-x
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DOI: https://doi.org/10.1007/s00109-010-0670-x