Metabolic reprogramming and inflammation act in concert to control vascular remodeling in hypoxic pulmonary hypertension

Journal of Applied Physiology

Volumn 119, Issue 10, 2015, Pages 1164-1172

  Stenmark, Kurt R ^a   Tuder, Rubin M ^b   El Kasmi, Karim C ^b  

^a University of Colorado Denver and Children s Hospital Colorado   (United States)

^b UNIVERSITY OF COLORADO SCHOOL OF MEDICINE   (United States)

Author keywords

Fibroblast; Glycolysis; HIF; IL 6; Macrophage

Indexed keywords

AUTACOID;

ANIMAL; HUMAN; HYPOXIA; INFLAMMATION; METABOLIC ACTIVATION; METABOLISM; PATHOLOGY; PHYSIOLOGY; PULMONARY HYPERTENSION; VASCULAR REMODELING;

ACTIVATION, METABOLIC; ANIMALS; HUMANS; HYPERTENSION, PULMONARY; HYPOXIA; INFLAMMATION; INFLAMMATION MEDIATORS; VASCULAR REMODELING;

EID: 84947205873     PISSN: 87507587     EISSN: 15221601     Source Type: Journal    
DOI: 10.1152/japplphysiol.00283.2015     Document Type: Review

References (105)

1. Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease: a clinical trial. Nocturnal Oxygen Therapy Trial Group. Ann Intern Med 93: 391-398, 1980.
2. Anwar A, Li M, Frid MG, Kumar B, Gerasimovskaya EV, Riddle SR, McKeon BA, Thukaram R, Meyrick BO, Fini MA, Stenmark KR. Osteopontin is an endogenous modulator of the constitutively activated phenotype of pulmonary adventitial fibroblasts in hypoxic pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 303: L1-L11, 2012.
3. Archer SL, Fang YH, Ryan JJ, Piao L. Metabolism and bioenergetics in the right ventricle and pulmonary vasculature in pulmonary hypertension. Pulm Circ 3: 144-152, 2013.
4. Augsten M, Hagglof C, Olsson E, Stolz C, Tsagozis P, Levchenko T, Frederick MJ, Borg A, Micke P, Egevad L, Ostman A. CXCL14 is an autocrine growth factor for fibroblasts and acts as a multi-modal stimulator of prostate tumor growth. Proc Natl Acad Sci USA 106: 3414-3419, 2009.
5. Baglole CJ, Ray DM, Bernstein SH, Feldon SE, Smith TJ, Sime PJ, Phipps RP. More than structural cells, fibroblasts create and orchestrate the tumor microenvironment. Immunol Invest 35: 297-325, 2006.
6. Barone F, Nayar S, Buckley CD. The role of non-hematopoietic stromal cells in the persistence of inflammation. Front Immunol 3: 416, 2012.
7. Barron L, Smith AM, El Kasmi KC, Qualls JE, Huang X, Cheever A, Borthwick LA, Wilson MS, Murray PJ, Wynn TA. Role of arginase 1 from myeloid cells in Th2-dominated lung inflammation. PloS One 8: e61961, 2013.
8. Buckley CD, Pilling D, Lord JM, Akbar AN, Scheel-Toellner D, Salmon M. Fibroblasts regulate the switch from acute resolving to chronic persistent inflammation. Trends Immunol 22: 199-204, 2001.
9. Burke DL, Frid MG, Kunrath CL, Karoor V, Anwar A, Wagner BD, Strassheim D, Stenmark KR. Sustained hypoxia promotes the development of a pulmonary artery-specific chronic inflammatory microenvironment. Am J Physiol Lung Cell Mol Physiol 297: L238-L250, 2009.
10. Carlsen J, Hasseriis Andersen K, Boesgaard S, Iversen M, Steinbruchel D, Bogelund Andersen C. Pulmonary arterial lesions in explanted lungs after transplantation correlate with severity of pulmonary hypertension in chronic obstructive pulmonary disease. J Heart Lung Transplant 32: 347-354, 2013.
11. Cavasin MA, Demos-Davies K, Horn TR, Walker LA, Lemon DD, Birdsey N, Weiser-Evans MC, Harral J, Irwin DC, Anwar A, Yeager ME, Li M, Watson PA, Nemenoff RA, Buttrick PM, Stenmark KR, McKinsey TA. Selective class I histone deacetylase inhibition suppresses hypoxia-induced cardiopulmonary remodeling through an antiproliferative mechanism. Circ Res 110: 739-748, 2012.
12. Chaffer CL, Weinberg RA. A perspective on cancer cell metastasis. Science 331: 1559-1564, 2011.
13. Chaudhri VK, Salzler GG, Dick SA, Buckman MS, Sordella R, Karoly ED, Mohney R, Stiles BM, Elemento O, Altorki NK, McGraw TE. Metabolic alterations in lung cancer-associated fibroblasts correlated with increased glycolytic metabolism of the tumor. Mol Cancer Res 11: 579-592, 2013.
14. Cheung HC, Corley LJ, Fuller GN, McCutcheon IE, Cote GJ. Polypyrimidine tract binding protein and Notch1 are independently re-expressed in glioma. Mod Pathol 19: 1034-1041, 2006.
15. Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R, Fleming MD, Schreiber SL, Cantley LC. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature 452: 230-233, 2008.
16. Colegio OR, Chu NQ, Szabo AL, Chu T, Rhebergen AM, Jairam V, Cyrus N, Brokowski CE, Eisenbarth SC, Phillips GM, Cline GW, Phillips AJ, Medzhitov R. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 513: 559-563, 2014.
17. Cottrill KA, Chan SY. Metabolic dysfunction in pulmonary hypertension: the expanding relevance of the Warburg effect. Eur J Clin Invest 43: 855-865, 2013.
18. Cuttica MJ, Kalhan R, Shlobin OA, Ahmad S, Gladwin M, Machado RF, Barnett SD, Nathan SD. Categorization and impact of pulmonary hypertension in patients with advanced COPD. Respir Med 104: 1877-1882, 2010.
19. Das M, Burns N, Wilson SJ, Zawada WM, Stenmark KR. Hypoxia exposure induces the emergence of fibroblasts lacking replication repressor signals of PKCzeta in the pulmonary artery adventitia. Cardiovasc Res 78: 440-448, 2008.
20. Demaria M, Poli V. PKM2, STAT3 and HIF-1alpha: The Warburg's vicious circle. JAKSTAT 1: 194-196, 2012.
21. Doherty JR, Cleveland JL. Targeting lactate metabolism for cancer therapeutics. J Clin Invest 123: 3685-3692, 2013.
22. Dromparis P, Michelakis ED. Mitochondria in vascular health and disease. Annu Rev Physiol 75: 95-126, 2013.
23. Dromparis P, Paulin R, Sutendra G, Qi AC, Bonnet S, Michelakis ED. Uncoupling protein 2 deficiency mimics the effects of hypoxia and endoplasmic reticulum stress on mitochondria and triggers pseudohypoxic pulmonary vascular remodeling and pulmonary hypertension. Circ Res 113: 126-136, 2013.
24. Duffield JS, Lupher M, Thannickal VJ, Wynn TA. Host responses in tissue repair and fibrosis. Annu Rev Pathol 8: 241-276, 2013.
25. Dvorak HF. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med 315: 1650-1659, 1986.
26. El Kasmi KC, Pugliese SC, Riddle SR, Poth JM, Anderson AL, Frid MG, Li M, Pullamsetti SS, Savai R, Nagel MA, Fini MA, Graham BB, Tuder RM, Friedman JE, Eltzschig HK, Sokol RJ, Stenmark KR. Adventitial fibroblasts induce a distinct proinflammatory/profibrotic macrophage phenotype in pulmonary hypertension. J Immunol 193: 597-609, 2014.
27. Everts B, Amiel E, Huang SC, Smith AM, Chang CH, Lam WY, Redmann V, Freitas TC, Blagih J, van der Windt GJ, Artyomov MN, Jones RG, Pearce EL, Pearce EJ. TLR-driven early glycolytic reprogramming via the kinases TBK1-IKKa supports the anabolic demands of dendritic cell activation. Nat Immunol 15: 323-332, 2014.
28. Everts B, Amiel E, van der Windt GJ, Freitas TC, Chott R, Yarasheski KE, Pearce EL, Pearce EJ. Commitment to glycolysis sustains survival of NO-producing inflammatory dendritic cells. Blood 120: 1422-1431, 2012.
29. Feig C, Jones JO, Kraman M, Wells RJ, Deonarine A, Chan DS, Connell CM, Roberts EW, Zhao Q, Caballero OL, Teichmann SA, Janowitz T, Jodrell DI, Tuveson DA, Fearon DT. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc Natl Acad Sci USA 110: 20212-20217, 2013.
30. Fijalkowska I, Xu W, Comhair SA, Janocha AJ, Mavrakis LA, Krishnamachary B, Zhen L, Mao T, Richter A, Erzurum SC, Tuder RM. Hypoxia inducible-factor1alpha regulates the metabolic shift of pulmonary hypertensive endothelial cells. Am J Pathol 176: 1130-1138, 2010.
31. Flavell SJ, Hou TZ, Lax S, Filer AD, Salmon M, Buckley CD. Fibroblasts as novel therapeutic targets in chronic inflammation. Br J Pharmacol 153, Suppl 1: S241-S246, 2008.
32. Freund-Michel V, Khoyrattee N, Savineau JP, Muller B, Guibert C. Mitochondria: roles in pulmonary hypertension. Int J Biochem Cell Biol 55: 93-97, 2014.
33. Frid MG, Brunetti JA, Burke DL, Carpenter TC, Davie NJ, Reeves JT, Roedersheimer MT, van Rooijen N, Stenmark KR. Hypoxiainduced pulmonary vascular remodeling requires recruitment of circulating mesenchymal precursors of a monocyte/macrophage lineage. Am J Pathol 168: 659-669, 2006.
34. Furuta M, Kozaki KI, Tanaka S, Arii S, Imoto I, Inazawa J. miR-124 and miR-203 are epigenetically silenced tumor-suppressive microRNAs in hepatocellular carcinoma. Carcinogenesis 31: 766-776, 2010.
35. Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell 140: 883-899, 2010.
36. Haigis MC, Sinclair DA. Mammalian sirtuins: biological insights and disease relevance. Annu Rev Pathol 5: 253-295, 2010.
37. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 144: 646-674, 2011.
38. Hassoun PM, Mouthon L, Barbera JA, Eddahibi S, Flores SC, Grimminger F, Jones PL, Maitland ML, Michelakis ED, Morrell NW, Newman JH, Rabinovitch M, Schermuly R, Stenmark KR, Voelkel NF, Yuan JX, Humbert M. Inflammation, growth factors, and pulmonary vascular remodeling. J Am Coll Cardiol 54: S10-S19, 2009.
39. Holt AP, Haughton EL, Lalor PF, Filer A, Buckley CD, Adams DH. Liver myofibroblasts regulate infiltration and positioning of lymphocytes in human liver. Gastroenterology 136: 705-714, 2009.
40. Huang SC, Everts B, Ivanova Y, O'Sullivan D, Nascimento M, Smith AM, Beatty W, Love-Gregory L, Lam WY, O'Neill CM, Yan C, Du H, Abumrad NA, Urban JF Jr, Artyomov MN, Pearce EL, Pearce EJ. Cell-intrinsic lysosomal lipolysis is essential for alternative activation of macrophages. Nat Immunol 15: 846-855, 2014.
41. Iijima J, Konno K, Itano N. Inflammatory alterations of the extracellular matrix in the tumor microenvironment. Cancers (Basel) 3: 3189-3205, 2011.
42. Kaufman J, Graf BA, Leung EC, Pollock SJ, Koumas L, Reddy SY, Blieden TM, Smith TJ, Phipps RP. Fibroblasts as sentinel cells: role of the CDcd40-CDcd40 ligand system in fibroblast activation and lung inflammation and fibrosis. Chest 120: 53S-55S, 2001.
43. Kessler R, Faller M, Weitzenblum E, Chaouat A, Aykut A, Ducolone A, Ehrhart M, Oswald-Mammosser M. "Natural history" of pulmonary hypertension in a series of 131 patients with chronic obstructive lung disease. Am J Respir Crit Care Med 164: 219-224, 2001.
44. Koppenol WH, Bounds PL, Dang CV. Otto Warburg's contributions to current concepts of cancer metabolism. Nat Rev Cancer 11: 325-337, 2011.
45. Krawczyk CM, Holowka T, Sun J, Blagih J, Amiel E, DeBerardinis RJ, Cross JR, Jung E, Thompson CB, Jones RG, Pearce EJ. Toll-like receptor-induced changes in glycolytic metabolism regulate dendritic cell activation. Blood 115: 4742-4749, 2010.
46. Kuang SQ, Geng L, Prakash SK, Cao JM, Guo S, Villamizar C, Kwartler CS, Peters AM, Brasier AR, Milewicz DM. Aortic remodeling after transverse aortic constriction in mice is attenuated with AT1 receptor blockade. Arterioscler Thromb Vasc Biol 33: 2172-2179, 2013.
47. Li M, Riddle SR, Frid MG, El Kasmi KC, McKinsey TA, Sokol RJ, Strassheim D, Meyrick B, Yeager ME, Flockton AR, McKeon BA, Lemon DD, Horn TR, Anwar A, Barajas C, Stenmark KR. Emergence of fibroblasts with a proinflammatory epigenetically altered phenotype in severe hypoxic pulmonary hypertension. J Immunol 187: 2711-2722, 2011.
48. Lv L, Li D, Zhao D, Lin R, Chu Y, Zhang H, Zha Z, Liu Y, Li Z, Xu Y, Wang G, Huang Y, Xiong Y, Guan KL, Lei QY. Acetylation targets the M2 isoform of pyruvate kinase for degradation through chaperonemediated autophagy and promotes tumor growth. Mol Cell 42: 719-730, 2011.
49. Mace TA, Ameen Z, Collins A, Wojcik S, Mair M, Young GS, Fuchs JR, Eubank TD, Frankel WL, Bekaii-Saab T, Bloomston M, Lesinski GB. Pancreatic cancer-associated stellate cells promote differentiation of myeloid-derived suppressor cells in a STAT3-dependent manner. Cancer Res 73: 3007-3018, 2013.
50. Makeyev EV, Zhang J, Carrasco MA, Maniatis T. The microRNA miR-124 promotes neuronal differentiation by triggering brain-specific alternative pre-mRNA splicing. Mol Cell 27: 435-448, 2007.
51. Maron BA, Choudhary G, Khan UA, Jankowich MD, McChesney H, Ferrazzani SJ, Gaddam S, Sharma S, Opotowsky AR, Bhatt DL, Rocco TP, Aragam JR. Clinical profile and underdiagnosis of pulmonary hypertension in US veteran patients. Circ Heart Fail 6: 906-912, 2013.
52. Marsboom G, Wietholt C, Haney CR, Toth PT, Ryan JJ, Morrow E, Thenappan T, Bache-Wiig P, Piao L, Paul J, Chen CT, Archer SL. Lung 18F-fluorodeoxyglucose positron emission tomography for diagnosis and monitoring of pulmonary arterial hypertension. Am J Respir Crit Care Med 185: 670-679, 2012.
53. Martinez-Outschoorn UE, Lisanti MP, Sotgia F. Catabolic cancerassociated fibroblasts transfer energy and biomass to anabolic cancer cells, fueling tumor growth. Semin Cancer Biol 25: 47-60, 2014.
54. Metallo CM, Vander Heiden MG. Metabolism strikes back: metabolic flux regulates cell signaling. Genes Dev 24: 2717-2722, 2010.
55. Michelakis ED, McMurtry MS, Wu XC, Dyck JR, Moudgil R, Hopkins TA, Lopaschuk GD, Puttagunta L, Waite R, Archer SL. 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, 2002.
56. Murray PJ, Wynn TA. Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol 11: 723-737, 2011.
57. O'Sullivan D, Pearce EL. Targeting T cell metabolism for therapy. Trends Immunol 36: 71-80, 2015.
58. Odegaard JI, Chawla A. Alternative macrophage activation and metabolism. Annu Rev Pathol 6: 275-297, 2011.
59. Ohlund D, Elyada E, Tuveson D. Fibroblast heterogeneity in the cancer wound. J Exp Med 211: 1503-1523, 2014.
60. Ostuni R, Kratochvill F, Murray PJ, Natoli G. Macrophages and cancer: from mechanisms to therapeutic implications. Trends Immunol 36: 229-239, 2015.
61. Otranto M, Sarrazy V, Bonte F, Hinz B, Gabbiani G, Desmouliere A. The role of the myofibroblast in tumor stroma remodeling. Cell Adh Migr 6: 203-219, 2012.
62. Palsson-McDermott EM, Curtis AM, Goel G, Lauterbach MA, Sheedy FJ, Gleeson LE, van den Bosch MW, Quinn SR, Domingo-Fernandez R, Johnston DG, Jiang JK, Israelsen WJ, Keane J, Thomas C, Clish C, Vanden Heiden M, Xavier RJ, O'Neill LA. Pyruvate kinase M2 regulates Hif-1alpha activity and IL-1beta induction and is a critical determinant of the Warburg effect in LPS-activated macrophages. Cell Metab 21: 65-80, 2015.
63. Palsson-McDermott EM, O'Neill LA. The Warburg effect then and now: from cancer to inflammatory diseases. Bioessays 35: 965-973, 2013.
64. Panzhinskiy E, Zawada WM, Stenmark KR, Das M. Hypoxia induces unique proliferative response in adventitial fibroblasts by activating PDGFbeta receptor-JNK1 signalling. Cardiovasc Res 95: 356-365, 2012.
65. Paulin R, Michelakis ED. The metabolic theory of pulmonary arterial hypertension. Circ Res 115: 148-164, 2014.
66. Pavlides S, Whitaker-Menezes D, Castello-Cros R, Flomenberg N, Witkiewicz AK, Frank PG, Casimiro MC, Wang C, Fortina P, Addya S, Pestell RG, Martinez-Outschoorn UE, Sotgia F, Lisanti MP. The reverse Warburg effect: aerobic glycolysis in cancer associated fibroblasts and the tumor stroma. Cell Cycle 8: 3984-4001, 2009.
67. Pearce EJ, Everts B. Dendritic cell metabolism. Nat Rev Immunol 15: 18-29, 2015.
68. Pesce JT, Ramalingam TR, Mentink-Kane MM, Wilson MS, El Kasmi KC, Smith AM, Thompson RW, Cheever AW, Murray PJ, Wynn TA. Arginase-1-expressing macrophages suppress Th2 cytokinedriven inflammation and fibrosis. PLoS Pathog 5: e1000371, 2009.
69. Piao L, Marsboom G, Archer SL. Mitochondrial metabolic adaptation in right ventricular hypertrophy and failure. J Mol Med (Berl) 88: 1011-1020, 2010.
70. Psaltis PJ, Puranik AS, Spoon DB, Chue CD, Hoffman SJ, Witt TA, Delacroix S, Kleppe LS, Mueske CS, Pan S, Gulati R, Simari RD. Characterization of a resident population of adventitial macrophage progenitor cells in postnatal vasculature. Circ Res 115: 364-375, 2014.
71. Pugliese SC, Poth JM, Fini MA, Olschewski A, El Kasmi KC, Stenmark KR. The role of inflammation in hypoxic pulmonary hypertension: from cellular mechanisms to clinical phenotypes. Am J Physiol Lung Cell Mol Physiol 308: L229-L252, 2015.
72. Qualls JE, Subramanian C, Rafi W, Smith AM, Balouzian L, DeFreitas AA, Shirey KA, Reutterer B, Kernbauer E, Stockinger S, Decker T, Miyairi I, Vogel SN, Salgame P, Rock CO, Murray PJ. Sustained generation of nitric oxide and control of mycobacterial infection requires argininosuccinate synthase 1. Cell Host Microbe 12: 313-323, 2012.
73. Rasanen K, Vaheri A. Activation of fibroblasts in cancer stroma. Exp Cell Res 316: 2713-2722, 2010.
74. Rodriguez-Prados JC, Traves PG, Cuenca J, Rico D, Aragones J, Martin-Sanz P, Cascante M, Bosca L. Substrate fate in activated macrophages: a comparison between innate, classic, and alternative activation. J Immunol 185: 605-614, 2010.
75. Savai R, Pullamsetti SS, Kolbe J, Bieniek E, Voswinckel R, Fink L, Scheed A, Ritter C, Dahal BK, Vater A, Klussmann S, Ghofrani HA, Weissmann N, Klepetko W, Banat GA, Seeger W, Grimminger F, Schermuly RT. Immune and inflammatory cell involvement in the pathology of idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 186: 897-908, 2012.
76. Seeger W, Adir Y, Barbera JA, Champion H, Coghlan JG, Cottin V, De Marco T, Galie N, Ghio S, Gibbs S, Martinez FJ, Semigran MJ, Simonneau G, Wells AU, Vachiery JL. Pulmonary hypertension in chronic lung diseases. J Am Coll Cardiol 62: D109-D116, 2013.
77. Servais C, Erez N. From sentinel cells to inflammatory culprits: cancerassociated fibroblasts in tumour-related inflammation. J Pathol 229: 198-207, 2013.
78. Simonneau G, Gatzoulis MA, Adatia I, Celermajer D, Denton C, Ghofrani A, Gomez Sanchez MA, Krishna Kumar R, Landzberg M, Machado RF, Olschewski H, Robbins IM, Souza R. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 62: D34-D41, 2013.
79. Sivakumar P, Ntolios P, Jenkins G, Laurent G. Into the matrix: targeting fibroblasts in pulmonary fibrosis. Curr Opin Pulm Med 18: 462-469, 2012.
80. Smith RS, Smith TJ, Blieden TM, Phipps RP. Fibroblasts as sentinel cells. Synthesis of chemokines and regulation of inflammation. Am J Pathol 151: 317-322, 1997.
81. Stenmark KR, Fagan KA, Frid MG. Hypoxia-induced pulmonary vascular remodeling: cellular and molecular mechanisms. Circ Res 99: 675-691, 2006.
82. Stenmark KR, Frid MG, Yeager M, Li M, Riddle S, McKinsey T, El Kasmi KC. Targeting the adventitial microenvironment in pulmonary hypertension: a potential approach to therapy that considers epigenetic change. Pulm Circ 2: 3-14, 2012.
83. Stenmark KR, Meyrick B, Galie N, Mooi WJ, McMurtry IF. Animal models of pulmonary arterial hypertension: the hope for etiological discovery and pharmacological cure. Am J Physiol Lung Cell Mol Physiol 297: L1013-L1032, 2009.
84. Stenmark KR, Nozik-Grayck E, Gerasimovskaya E, Anwar A, Li M, Riddle S, Frid M. The adventitia: essential role in pulmonary vascular remodeling. Compr Physiol 1: 141-161, 2011.
85. Stenmark KR, Yeager ME, El Kasmi KC, Nozik-Grayck E, Gerasimovskaya EV, Li M, Riddle SR, Frid MG. The adventitia: essential regulator of vascular wall structure and function. Annu Rev Physiol 75: 23-47, 2013.
86. Sutendra G, Bonnet S, Rochefort G, Haromy A, Folmes KD, Lopaschuk GD, Dyck JR, Michelakis ED. Fatty acid oxidation and malonyl-CoA decarboxylase in the vascular remodeling of pulmonary hypertension. Sci Transl Med 2: 44ra58, 2010.
87. Tang PC, Qin L, Zielonka J, Zhou J, Matte-Martone C, Bergaya S, van Rooijen N, Shlomchik WD, Min W, Sessa WC, Pober JS, Tellides G. MyD88-dependent, superoxide-initiated inflammation is necessary for flow-mediated inward remodeling of conduit arteries. J Exp Med 205: 3159-3171, 2008.
88. Tannahill GM, Curtis AM, Adamik J, Palsson-McDermott EM, McGettrick AF, Goel G, Frezza C, Bernard NJ, Kelly B, Foley NH, Zheng L, Gardet A, Tong Z, Jany SS, Corr SC, Haneklaus M, Caffrey BE, Pierce K, Walmsley S, Beasley FC, Cummins E, Nizet V, Whyte M, Taylor CT, Lin H, Masters SL, Gottlieb E, Kelly VP, Clish C, Auron PE, Xavier RJ, O'Neill LA. Succinate is an inflammatory signal that induces IL-1beta through HIF-1alpha. Nature 496: 238-242, 2013.
89. Tellides G, Pober JS. Inflammatory and immune responses in the arterial media. Circ Res 116: 312-322, 2015.
90. Torres S, Bartolome RA, Mendes M, Barderas R, Fernandez-Acenero MJ, Pelaez-Garcia A, Pena C, Lopez-Lucendo M, Villar-Vazquez R, de Herreros AG, Bonilla F, Casal JI. Proteome profiling of cancer-associated fibroblasts identifies novel proinflammatory signatures and prognostic markers for colorectal cancer. Clin Cancer Res 19: 6006-6019, 2013.
91. Tuder RM, Archer SL, Dorfmuller P, Erzurum SC, Guignabert C, Michelakis E, Rabinovitch M, Schermuly R, Stenmark KR, Morrell NW. Relevant issues in the pathology and pathobiology of pulmonary hypertension. J Am Coll Cardiol 62: D4-D12, 2013.
92. Tuder RM, Davis LA, Graham BB. Targeting energetic metabolism: a new frontier in the pathogenesis and treatment of pulmonary hypertension. Am J Respir Crit Care Med 185: 260-266, 2012.
93. van Nieuwenhoven FA, Turner NA. The role of cardiac fibroblasts in the transition from inflammation to fibrosis following myocardial infarction. Vascul Pharmacol 58: 182-188, 2013.
94. Vats D, Mukundan L, Odegaard JI, Zhang L, Smith KL, Morel CR, Wagner RA, Greaves DR, Murray PJ, Chawla A. Oxidative metabolism and PGC-1beta attenuate macrophage-mediated inflammation. Cell Metab 4: 13-24, 2006.
95. Wang D, Zhang H, Li M, Frid MG, Flockton AR, McKeon BA, Yeager ME, Fini MA, Morrell NW, Pullamsetti SS, Velegala S, Seeger W, McKinsey TA, Sucharov CC, Stenmark KR. MicroRNA-124 controls the proliferative, migratory, and inflammatory phenotype of pulmonary vascular fibroblasts. Circ Res 114: 67-78, 2014.
96. Wang J, Ying G, Wang J, Jung Y, Lu J, Zhu J, Pienta KJ, Taichman RS. Characterization of phosphoglycerate kinase-1 expression of stromal cells derived from tumor microenvironment in prostate cancer progression. Cancer Res 70: 471-480, 2010.
97. Wang P, Chen L, Zhang J, Chen H, Fan J, Wang K, Luo J, Chen Z, Meng Z, Liu L. Methylation-mediated silencing of the miR-124 genes facilitates pancreatic cancer progression and metastasis by targeting Rac1. Oncogene 33: 514-524, 2014.
98. Wellen KE, Thompson CB. A two-way street: reciprocal regulation of metabolism and signalling. Nat Rev Mol Cell Biol 13: 270-276, 2012.
99. Wynn TA. Cellular and molecular mechanisms of fibrosis. J Pathol 214: 199-210, 2008.
100. Yang P, Li Z, Fu R, Wu H, Li Z. Pyruvate kinase M2 facilitates colon cancer cell migration via the modulation of STAT3 signalling. Cell Signal 26: 1853-1862, 2014.
101. Yang P, Li Z, Li H, Lu Y, Wu H, Li Z. Pyruvate kinase M2 accelerates pro-inflammatory cytokine secretion and cell proliferation induced by lipopolysaccharide in colorectal cancer. Cell Signal 27: 1525-1532, 2015.
102. Zhao L, Ashek A, Wang L, Fang W, Dabral S, Dubois O, Cupitt J, Pullamsetti SS, Cotroneo E, Jones H, Tomasi G, Nguyen QD, Aboagye EO, El-Bahrawy MA, Barnes G, Howard LS, Gibbs JS, Gsell W, He JG, Wilkins MR. Heterogeneity in lung (18)FDG uptake in pulmonary arterial hypertension: potential of dynamic (18)FDG positron emission tomography with kinetic analysis as a bridging biomarker for pulmonary vascular remodeling targeted treatments. Circulation 128: 1214-1224, 2013.
103. Zhao L, Chen CN, Hajji N, Oliver E, Cotroneo E, Wharton J, Wang D, Li M, McKinsey TA, Stenmark KR, Wilkins MR. Histone deacetylation inhibition in pulmonary hypertension: therapeutic potential of valproic acid and suberoylanilide hydroxamic acid. Circulation 126: 455-467, 2012.
104. Zhao S, Xu W, Jiang W, Yu W, Lin Y, Zhang T, Yao J, Zhou L, Zeng Y, Li H, Li Y, Shi J, An W, Hancock SM, He F, Qin L, Chin J, Yang P, Chen X, Lei Q, Xiong Y, Guan KL. Regulation of cellular metabolism by protein lysine acetylation. Science 327: 1000-1004, 2010.
105. Zhou J, Tang PC, Qin L, Gayed PM, Li W, Skokos EA, Kyriakides TR, Pober JS, Tellides G. CXCR3-dependent accumulation and activation of perivascular macrophages is necessary for homeostatic arterial remodeling to hemodynamic stresses. J Exp Med 207: 1951-1966, 2010.