MTOR and vascular remodeling in lung diseases: Current challenges and therapeutic prospects

FASEB Journal

Volumn 27, Issue 5, 2013, Pages 1796-1807

  Goncharova, Elena A ^a  

^a UNIVERSITY OF PENNSYLVANIA   (United States)

Author keywords

MTORC1; MTORC2; Pulmonary hypertension; Rapamycin

Indexed keywords

CALCIUM ION; MAMMALIAN TARGET OF RAPAMYCIN; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 2; PROTEIN KINASE B; RHO KINASE; SERUM AND GLUCOCORTICOID REGULATED KINASE 1;

APOPTOSIS; AUTOPHAGY; CELL PROLIFERATION; CELL SURVIVAL; CYTOSKELETON; GLYCOLYSIS; HUMAN; HYPOXIA; LIPOGENESIS; LUNG BLOOD VESSEL; LUNG DISEASE; PRIORITY JOURNAL; PROTEIN FUNCTION; PROTEIN SYNTHESIS; PULMONARY HYPERTENSION; REVIEW; SIGNAL TRANSDUCTION; TISSUE REGENERATION;

ANOXIA; APOPTOSIS; AUTOPHAGY; CALCIUM CHANNELS; CELL PROLIFERATION; HUMANS; HYPERTENSION, PULMONARY; INTERCELLULAR SIGNALING PEPTIDES AND PROTEINS; LUNG; MULTIPROTEIN COMPLEXES; MUSCLE, SMOOTH, VASCULAR; PULMONARY ARTERY; PULMONARY CIRCULATION; SIGNAL TRANSDUCTION; SIROLIMUS; TOR SERINE-THREONINE KINASES; VASCULAR DISEASES;

MAMMALIA;

EID: 84877121075     PISSN: None     EISSN: 15306860     Source Type: Journal    
DOI: 10.1096/fj.12-222224     Document Type: Review

References (100)

1. Laplante, M., and Sabatini, D. M. (2012) mTOR signaling in growth control and disease. Cell 149, 274-293
2. Morrell, N. W., Adnot, S., Archer, S. L., Dupuis, J., Jones, P. L., MacLean, M. R., McMurtry, I. F., Stenmark, K. R., Thistlethwaite, P. A., Weissmann, N., Yuan, J. X. J., and Weir, E. K. (2009) Cellular and molecular basis of pulmonary arterial hypertension. J. Am. Coll. Cardiol. 54, S20-S31
3. Simonneau, G., Robbins, I. M., Beghetti, M., Channick, R. N., Delcroix, M., Denton, C. P., Elliott, C. G., Gaine, S. P., Gladwin, M. T., Jing, Z. C., Krowka, M. J., Langleben, D., Nakanishi, N., and Souza, R. (2009) Updated clinical classification of pulmonary hypertension, J. Am. Coll. Cardiol. 54, S43-S54
4. Behr, J., and Ryu, J. H. (2008) Pulmonary hypertension in interstitial lung disease. Eur. Respir. J. 31, 1357-1367
5. Barbera, J. A., Peinado, V. I., and Santos, S. (2003) Pulmonary hypertension in chronic obstructive pulmonary disease, Eur. Respir. J. 21, 892-905
6. Cottin, V., Harari, S., Humbert, M., Mal, H., Dorfmüller, P., Jaïs, X., Reynaud-Gaubert, M., Prevot, G., Lazor, R., Taillé, C., Lacronique, J., Zeghmar, S., Simonneau, G., Cordier, J.F., and Groupe dEtudes et de Recherche sur les Maladies "Orphelines" Pulmonaires (GERM"O"P) (2012) Pulmonary hypertension in lymphangioleiomyomatosis: characteristics in 20 patients. Eur. Respir. J. 40, 630-640
7. Tuder, R. M., Marecki, J. C., Richter, A., Fijalkowska, I., and Flores, S. (2007) Pathology of pulmonary hypertension. Clin. Chest Med. 28, 23-42
8. Archer, S. L., Gomberg-Maitland, M., Maitland, M. L., Rich, S., Garcia, J. G. N., and Weir, E. K. (2008) Mitochondrial metabolism, redox signaling, and fusion: a mitochondria-ROS-HIF-1-Kv1.5 O2-sensing pathway at the intersection of pulmonary hypertension and cancer. Am. J. Physiol. Heart Circ. Physiol. 294, H570-H578
9. Xu, W., Koeck, T., Lara, A. R., Neumann, D., DiFilippo, F. P., Koo, M., Janocha, A. J., Masri, F. A., Arroliga, A. C., Jennings, C., Dweik, R. A., Tuder, R. M., Stuehr, D. J., and Erzurum, S. C. (2007) Alterations of cellular bioenergetics in pulmonary artery endothelial cells. Proc. Natl. Acad. Sci. U. S. A. 104, 1342-1347
10. Fijalkowska, I., Xu, W., Comhair, S. A., Janocha, A. J., Mavrakis, L. A., Krishnamachary, B., Zhen, L., Mao, T., Richter, A., Erzurum, S. C., and Tuder, R. M. (2010) Hypoxia-induciblefactor1-regulates the metabolic shift of pulmonary hypertensive endothelial cells. Am. J. Pathol. 176, 1130-1138
11. Sutendra, G., Bonnet, S., Rochefort, G., Haromy, A., Folmes, K. D., Lopaschuk, G. D., Dyck, J. R. B., and Michelakis, E. D. (2010) Fatty acid oxidation and malonyl-CoA decarboxylase in the vascular remodeling of pulmonary hypertension. Sci. Transl. Med. 2, 44ra58
12. Tuder, R. M., Davis, L. A., and Graham, B. B. (2012) Targeting energetic metabolism. Am. J. Respir. Crit. Care Med. 185, 260-266
13. Jacinto, E., Loewith, R., Schmidt, A., Lin, S., Ruegg, M. A., Hall, A., and Hall, M. N. (2004) Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat. Cell Biol. 6, 1122-1128
14. Kim, D. H., Sarbassov, D. D., Ali, S. M., Latek, R. R., Guntur, K. V. P., Erdjument-Bromage, H., Tempst, P., and Sabatini, D. M. (2003) GL, a positive regulator of the rapamycinsensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol. Cell 11, 895-904
15. Peterson, T. R., Laplante, M., Thoreen, C. C., Sancak, Y., Kang, S. A., Kuehl, W. M., Gray, N. S., and Sabatini, D. M. (2009) DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell 137, 873-886
16. Kaizuka, T., Hara, T., Oshiro, N., Kikkawa, U., Yonezawa, K., Takehana, K., Iemura, S., Natsume, T., and Mizushima, N. (2010) Tti1 and Tel2 are critical factors in mammalian target of rapamycin complex assembly. J. Biol. Chem. 285, 20109-20116
17. Brown, E. J., Beal, P. A., Keith, C. T., Chen, J., Shin, T. B., and Schreiber, S. L. (1995) Control of p70 S6 kinase by kinase activity of FRAP in vivo. Nature 377, 441-446
18. Brunn, G. J., Hudson, C. C., Sekulic, A., Williams, J. M., Hosoi, H., Houghton, P. J., Lawrence J.C., Jr., and Abraham, R. T. (1997) Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin. Science 277, 99-101
19. Kim, D. H., Sarbassov, D. D., Ali, S. M., King, J. E., Latek, R. R., Erdjument-Bromage, H., Tempst, P., and Sabatini, D. M. (2002) mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110, 163-175
20. Sarbassov, D. D., Ali, S. M., Sengupta, S., Sheen, J. H., Hsu, P. P., Bagley, A. F., Markhard, A. L., and Sabatini, D. M. (2006) Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol. Cell 22, 159-168
21. Barilli, A., Visigalli, R., Sala, R., Gazzola, G. C., Parolari, A., Tremoli, E., Bonomini, S., Simon, A., Closs, E. I., DallAsta, V., and Bussolati, O. (2008) In human endothelial cells rapamycin causes mTORC2 inhibition and impairs cell viability and function. Cardiovasc. Res. 78, 563-571
22. Li, W., Petrimpol, M., Molle, K. D., Hall, M. N., Battegay, E. J., and Humar, R. (2007) Hypoxia-induced endothelial proliferation requires both mTORC1 and mTORC2. Circ. Res. 100, 79-87
23. Inoki, K., Li, Y., Xu, T., and Guan, K. L. (2003) Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev. 17, 1829-1834
24. Tee, A. R., Manning, B. D., Roux, P. P., Cantley, L. C., and Blenis, J. (2003) Tuberous sclerosis complex gene products, tuberin and hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Curr. Biol. 13, 1259-1268
25. Krymskaya, V. P., and Goncharova, E. A. (2009) PI3K/mTORC1 Activation in hamartoma syndromes: therapeutic prospects. Cell Cycle 8, 403-413
26. Laplante, M., and Sabatini, D. M. (2009) mTOR signaling at a glance. J. Cell Sci. 122, 3589-3594
27. Kalender, A., Selvaraj, A., Kim, S. Y., Gulati, P., Brûlé, S., Viollet, B., Kemp, B. E., Bardeesy, N., Dennis, P. B., Schlager, J. J., Marette, A., Kozma, S. C., and Thomas, G. (2010) Metformin, independent of AMPK, inhibits mTORC1 in a Rag GTPase-dependent manner. Cell Metab. 11, 390-401
28. Sancak, Y., Peterson, T. R., Shaul, Y. D., Lindquist, R. A., Thoreen, C. C., Bar-Peled, L., and Sabatini, D. M. (2008) The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 320, 1496-1501
29. Shaw, R. J. (2009) LKB1 and AMP-activated protein kinase control of mTOR signalling and growth. Acta Physiol. 196, 65-80
30. Schneider, A., Younis, R. H., and Gutkind, J. S. (2008) Hypoxia-induced energy stress inhibits the mTOR pathway by activating an AMPK/REDD1 signaling axis in head and neck squamous cell carcinoma. Neoplasia 10, 1295-1302
31. Brugarolas, J., Lei, K., Hurley, R. L., Manning, B. D., Reiling, J. H., Hafen, E., Witters, L. A., Ellisen, L. W., and Kaelin, W. G., Jr. (2004) Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev. 18, 2893-2904
32. Ma, X. M., and Blenis, J. (2009) Molecular mechanisms of mTOR-mediated translational control. Nat. Rev. Mol. Cell Biol. 10, 307-318
33. Laplante, M., and Sabatini, D. M. (2009) An emerging role of mTOR in lipid biosynthesis. Curr. Biol. 19, R1046-R1052
34. Toschi, A., Lee, E., Gadir, N., Ohh, M., and Foster, D. A. (2008) Differential dependence of hypoxia-inducible factors 1 and 2 on mTORC1 and mTORC2. J. Biol. Chem. 283, 34495-34499
35. Marin-Hernandez, A., Gallardo-Perez, J. C., Ralph, S. J., Rodriguez-Enriquez, S., and Moreno-Sanchez, R. (2009) HIF-1 modulates energy metabolism in cancer cells by inducing overexpression of specific glycolytic isoforms. Mini Rev. Med. Chem. 9, 1084-1101
36. Düvel, K., Yecies, J. L., Menon, S., Raman, P., Lipovsky, A. I., Souza, A. L., Triantafellow, E., Ma, Q., Gorski, R., Cleaver, S., Vander Heiden, M. G., MacKeigan, J. P., Finan, P. M., Clish, C. B., Murphy, L. O., and Manning, B. D. (2010) Activation of a metabolic gene regulatory network downstream of mTOR complex Mol. Cell 39, 171-183
37. Hands, S. L., Proud, C. G., and Wyttenbach, A. (2009) mTORs role in ageing: protein synthesis or autophagy? Aging 1, 586-597
38. Carracedo, A., Ma, L., Teruya-Feldstein, J., Rojo, F., Salmena, L., Alimonti, A., Egia, A., Sasaki, A. T., Thomas, G., Kozma, S. C., Papa, A., Nardella, C., Cantley, L. C., Baselga, J., and Pandolfi, P. P. (2008) Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J. Clin. Invest. 118, 3065-3074
39. Sarbassov, D. D., Guertin, D. A., Ali, S. M., and Sabatini, D. M. (2005) Phosphorylation and regulation of Akt/PKB by the Rictor-mTOR complex. Science 307, 1098-1101
40. Guertin, D. A., Stevens, D. M., Thoreen, C. C., Burds, A. A., Kalaany, N. Y., Moffat, J., Brown, M., Fitzgerald, K. J., and Sabatini, D. M. (2006) Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKC, but Not S6K1. Dev. Cell 11, 859-871
41. Krymskaya, V. P., Snow, J., Cesarone, G., Khavin, I., Goncharov, D. A., Lim, P. N., Veasey, S. C., Ihida-Stansbury, K., Jones, P. L., and Goncharova, E. A. (2011) mTOR is required for pulmonary arterial vascular smooth muscle cell proliferation under chronic hypoxia. FASEB J. 25, 1922-1933
42. Roulin, D., Cerantola, Y., Dormond-Meuwly, A., Demartines, N., and Dormond, O. (2010) Targeting mTORC2 inhibits colon cancer cell proliferation in vitro and tumor formation in vivo. Mol. Cancer 9, 57
43. Gulati, N., Karsy, M., Albert, L., Murali, R., and Jhanwar-Uniyal, M. (2009) Involvement of mTORC1 and mTORC2 in regulation of glioblastoma multiforme growth and motility. Int. J. Oncol. 35, 731-740
44. Carayol, N., Vakana, E., Sassano, A., Kaur, S., Goussetis, D. J., Glaser, H., Druker, B. J., Donato, N. J., Altman, J. K., Barr, S., and Platanias, L. C. (2010) Critical roles for mTORC2-and rapamycin-insensitive mTORC1-complexes in growth and survival of BCR-ABL-expressing leukemic cells. Proc. Natl. Acad. Sci. U. S. A. 107, 12469-12474
45. Hsu, P. P., and Sabatini, D. M. (2008) Cancer cell metabolism: Warburg and beyond. Cell 134, 703-707
46. Manning, B. D., and Cantley, L. C. (2007) AKT/PKB signaling: navigating downstream. Cell 129, 1261-1274
47. Sarbassov, D. D., Ali, S. M., Kim, D. H., Guertin, D. A., Latek, R. R., Erdjument-Bromage, H., Tempst, P., and Sabatini, D. M. (2004) Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and Raptor-independent pathway that regulates the cytoskeleton. Curr. Biol. 14, 1296-1302
48. Benisty, J. I., McLaughlin, V. V., Landzberg, M. J., Rich, J. D., Newburger, J. W., Rich, S., and Folkman, J. (2004) Elevated basic fibroblast growth factor levels in patients with pulmonary arterial hypertension. Chest 126, 1255-1261
49. Izikki, M., Guignabert, C., Fadel, E., Humbert, M., Tu, L., Zadigue, P., Dartevelle, P., Simonneau, G., Adnot, S., Maitre, B., Raffestin, B., and Eddahibi, S. (2009) Endothelial-derived FGF2 contributes to the progression of pulmonary hypertension in humans and rodents. J. Clin. Invest. 119, 512-523
50. Geiger, R., Berger, R. M. F., Hess, J., Bogers, A. J. J. C., Sharma, H. S., and Mooi, W. J. (2000) Enhanced expression of vascular endothelial growth factor in pulmonary plexogenic arteriopathy due to congenital heart disease. J. Pathol. 191, 202-207
51. Tuder, R. M., Chacon, M., Alger, L., Wang, J., Taraseviciene-Stewart, L., Kasahara, Y., Cool, C. D., Bishop, A. E., Geraci, M. W., Semenza, G. L., Yacoub, M., Polak, J. M., and Voelkel, N. F. (2001) Expression of angiogenesis-related molecules in plexiform lesions in severe pulmonary hypertension: evidence for a process of disordered angiogenesis. J. Pathol. 195, 367-374
52. Schermuly, R. T., Dony, E., Ghofrani, H. A., Pullamsetti, S., Savai, R., Roth, M., Sydykov, A., Lai, Y. J., Weissmann, N., Seeger, W., and Grimminger, F. (2005) Reversal of experimental pulmonary hypertension by PDGF inhibition. J. Clin. Invest. 115, 2811-2821
53. Merklinger, S. L., Jones, P. L., Martinez, E. C., and Rabinovitch, M. (2005) Epidermal growth factor receptor blockade mediates smooth muscle cell apoptosis and improves survival in rats with pulmonary hypertension. Circulation 112, 423-431
54. Goncharova, E. A., Ammit, A. J., Irani, C., Carroll, R. G., Eszterhas, A. J., Panettieri, R. A., and Krymskaya, V. P. (2002) PI3K is required for proliferation and migration of human pulmonary vascular smooth muscle cells. Am. J. Physiol. Lung Cell. Mol. Physiol. 283, L354-L363
55. Deng, H., Hershenson, M. B., Lei, J., Anyanwu, A. C., Pinsky, D. J., and Bentley, J. K. (2010) Pulmonary artery smooth muscle hypertrophy: roles of glycogen synthase kinase-3 and p70 ribosomal S6 kinase, Am. J. Physiol. Lung Cell. Mol. Physiol. 298, L793-L803
56. Hida, W., Tun, Y. E., Kikuchi, Y., Okabe, S., and Shirato, K. (2002) Pulmonary hypertension in patients with chronic obstructive pulmonary disease: recent advances in pathophysiology and management. Respirology 7, 3-13
57. Wilkins, M. R. (2012) Pulmonary hypertension: the science behind the disease spectrum. Eur. Respir. Rev. 21, 19-26
58. Eddahibi, S., Guignabert, C., Barlier-Mur, A. M., Dewachter, L., Fadel, E., Dartevelle, P., Humbert, M., Simonneau, G., Hanoun, N., Saurini, F., Hamon, M., and Adnot, S. (2006) Cross talk between endothelial and smooth muscle cells in pulmonary hypertension. Circulation 113, 1857-1864
59. Liu, Y., and Fanburg, B. L. (2006) Serotonin-induced growth of pulmonary artery smooth muscle requires activation of phosphatidylinositol 3-kinase/serine-threonine protein kinase B/mammalian target of rapamycin/p70 ribosomal S6 kinase Am. J. Respir. Cell Mol. Biol. 34, 182-191
60. Yu, Y., Fantozzi, I., Remillard, C. V., Landsberg, J. W., Kunichika, N., Platoshyn, O., Tigno, D. D., Thistlethwaite, P. A., Rubin, L. J., and Yuan, J. X. J. (2004) Enhanced expression of transient receptor potential channels in idiopathic pulmonary arterial hypertension. Proc. Natl. Acad. Sci. U. S. A. 101, 13861-13866
61. Ogawa, A., Firth, A. L., Yao, W., Madani, M. M., Kerr, K. M., Auger, W. R., Jamieson, S. W., Thistlethwaite, P. A., and Yuan, J. X. J. (2009) Inhibition of mTOR attenuates store-operated Ca2 entry in cells from endarterectomized tissues of patients with chronic thromboembolic pulmonary hypertension. Am. J. Physiol. Lung Cell. Mol. Physiol. 297, L666-L676
62. MacMillan, D., and McCarron, J. G. (2009) Regulation by FK506 and rapamycin of Ca2 release from the sarcoplasmic reticulum in vascular smooth muscle: the role of FK506 binding proteins and mTOR. Br. J. Pharmacol. 158, 1112-1120
63. Ghofrani, H. A., Voswinckel, R., Reichenberger, F., Weissmann, N., Schermuly, R. T., Seeger, W., and Grimminger, F. (2006) Hypoxia-and non-hypoxia-related pulmonary hypertension-established and new therapies. Cardiovasc. Res. 72, 30-40
64. Arsham, A. M., Howell, J. J., and Simon, M. C. (2003) A novel hypoxia-inducible factor-independent hypoxic response regulating mammalian target of rapamycin and its targets. J. Biol. Chem. 278, 29655-29660
65. Liu, L., Cash, T. P., Jones, R. G., Keith, B., Thompson, C. B., and Simon, M. C. (2006) Hypoxia-induced energy stress regulates mRNA translation and cell growth. Mol. Cell 21, 521-531
66. Wouters, B. G., and Koritzinsky, M. (2008) Hypoxia signalling through mTOR and the unfolded protein response in cancer. Nat. Rev. Cancer 8, 851-864
67. Kourembanas, S., Marsden, P. A., McQuillan, L. P., and Faller, D. V. (1991) Hypoxia induces endothelin gene expression and secretion in cultured human endothelium. J. Clin. Invest. 88, 1054-1057
68. Kourembanas, S., Hannan, R. L., and Faller, D. V. (1990) Oxygen tension regulates the expression of the platelet-derived growth factor-B chain gene in human endothelial cells. J. Clin. Invest. 86, 670-674
69. Eddahibi, S., Fabre, V., Boni, C., Martres, M. P., Raffestin, B., Hamon, M., and Adnot, S. (1999) Induction of serotonin transporter by hypoxia in pulmonary vascular smooth muscle cells: relationship with the mitogenic action of serotonin. Circ. Res. 84, 329-336
70. Rabinovitch, M. (2001) Pathobiology of pulmonary hypertension: extracellular matrix. Clin. Chest Med. 22, 433-449
71. Stenmark, K. R., Fagan, K. A., and Frid, M. G. (2006) Hypoxiainduced pulmonary vascular remodeling. Circ. Res. 99, 675-691
72. Stenmark, K. R., Frid, M. G., Yeager, M., Li, M., Riddle, S., McKinsey, T., and El Kasmi, K. C. (2012) Targeting the adventitial microenvironment in pulmonary hypertension: a potential approach to therapy that considers epigenetic change. Pulm. Circ. 2, 3-14
73. Ambalavanan, N., Bulger, A., and Philips III, J. B. (1999) Hypoxia-induced release of peptide growth factors from neonatal porcine pulmonary artery smooth muscle cells. Neonatology 76, 311-319
74. Lin, M. J., Leung, G. P. H., Zhang, W. M., Yang, X. R., Yip, K. P., Tse, C. M., and Sham, J. S. K. (2004) Chronic hypoxia-induced upregulation of store-operated and receptor-operated Ca2 channels in pulmonary arterial smooth muscle cells. Circ. Res. 95, 496-505
75. Broughton, B. R. S., Jernigan, N. L., Norton, C. E., Walker, B. R., and Resta, T. C. (2010) Chronic hypoxia augments depolarization-induced Ca2 sensitization in pulmonary vascular smooth muscle through superoxide-dependent stimulation of RhoA. Am. J. Physiol. Lung Cell. Mol. Physiol. 298, L232-L242
76. Zhou, W., Dasgupta, C., Negash, S., and Raj, J. U. (2007) Modulation of pulmonary vascular smooth muscle cell phenotype in hypoxia: role of cGMP-dependent protein kinase. Am. J. Physiol. Lung Cell. Mol. Physiol. 292, L1459-L1466
77. Humar, R., Kiefer, F. N., Berns, H., Resink, T. J., and Battegay, E. J. (2002) Hypoxia enhances vascular cell proliferation and angiogenesis in vitro via rapamycin (mTOR)-dependent signaling, FASEB J. 16, 771-780
78. Gerasimovskaya, E. V., Tucker, D. A., and Stenmark, K. R. (2005) Activation of phosphatidylinositol 3-kinase, Akt, and mammalian target of rapamycin is necessary for hypoxiainduced pulmonary artery adventitial fibroblast proliferation. J. Appl. Physiol. 98, 722-731
79. Paddenberg, R., Stieger, P., von Lilien, A. L., Faulhammer, P., Goldenberg, A., Tillmanns, H., Kummer, W., and Braun-Dullaeus, R. C. (2007) Rapamycin attenuates hypoxia-induced pulmonary vascular remodeling and right ventricular hypertrophy in mice. Resp. Res. 8, 15
80. Agard, C., Rolli-Derkinderen, M., Dumas-de-La-Roque, E., Rio, M., Sagan, C., Savineau, J. P., Loirand, G., and Pacaud, P. (2009) Protective role of the antidiabetic drug metformin against chronic experimental pulmonary hypertension. Br. J. Pharmacol. 158, 1285-1294
81. Archer, S. L., Weir, E. K., and Wilkins, M. R. (2010) Basic science of pulmonary arterial hypertension for clinicians. Circulation 121, 2045-2066
82. Dennis, P. B., Jaeschke, A., Saitoh, M., Fowler, B., Kozma, S. C., and Thomas, G. (2001) Mammalian TOR: a homeostatic ATP sensor. Science 294, 1102-1105
83. Fagan, K. A., Oka, M., Bauer, N. R., Gebb, S. A., Ivy, D. D., Morris, K. G., and McMurtry, I. F. (2004) Attenuation of acute hypoxic pulmonary vasoconstriction and hypoxic pulmonary hypertension in mice by inhibition of Rho-kinase, Am. J. Physiol. Lung Cell. Mol. Physiol. 287, L656-L664
84. Hyvelin, J. M., Howell, K., Nichol, A., Costello, C. M., Preston, R. J., and McLoughlin, P. (2005) Inhibition of Rho-kinase attenuates hypoxia-induced angiogenesis in the pulmonary circulation. Circ. Res. 97, 185-191
85. Zhang, S., Fantozzi, I., Tigno, D. D., Yi, E. S., Platoshyn, O., Thistlethwaite, P. A., Kriett, J. M., Yung, G., Rubin, L. J., and Yuan, J. X. J. (2003) Bone morphogenetic proteins induce apoptosis in human pulmonary vascular smooth muscle cells. Am. J. Physiol. Lung Cell. Mol. Physiol. 285, L740-L754
86. McMurtry, M. S., Bonnet, S., Michelakis, E. D., Bonnet, S., Haromy, A., and Archer, S. L. (2007) Statin therapy, alone or with rapamycin, does not reverse monocrotaline pulmonary arterial hypertension: the rapamcyin- atorvastatin-simvastatin study. Am. J. Physiol. Lung Cell. Mol. Physiol. 293, L933-L940
87. Reddy, M. K., Vasir, J. K., Sahoo, S. K., Jain, T. K., Yallapu, M. M., and Labhasetwar, V. (2008) Inhibition of apoptosis through localized delivery of rapamycin-loaded nanoparticles prevented neointimal hyperplasia and reendothelialized injured artery/clinical perspective. Circ. Cardiovasc. Interv. 1, 209-216
88. Sahai, E., and Marshall, C. J. (2002) Rho-GTPases and cancer. Nat. Rev. Cancer 2, 133-142
89. Hassoun, P. M., Mouthon, L., Barbera, J.A., Eddahibi, S., Flores, S. C., Grimminger, F., Jones, P. L., Maitland, M. L., Michelakis, E. D., Morrell, N. W., Newman, J. H., Rabinovitch, M., Schermuly, R. T., Stenmark, K. R., Voelkel, N. F., Yuan, J. X. J., and Humbert, M. (2009) Inflammation, growth factors, and pulmonary vascular remodeling, J. Am. Coll. Cardiol. 54, S10-S19
90. Weichhart, T., and Säemann, M. D. (2009) The multiple facets of mTOR in immunity. Trends Immunol. 30, 218-226
91. Mathew, R., Karantza-Wadsworth, V., and White, E. (2007) Role of autophagy in cancer. Nat. Rev. Cancer 7, 961-967
92. Patel, A.S., Morse, D., and Choi, A. M. K. (2013) Regulation and functional significance of autophagy in respiratory cell biology and disease. Am. J. Respir. Cell Mol. Biol. 48, 1-9
93. Morice, M. C., Serruys, P. W., Sousa, J. E., Fajadet, J., Ban Hayashi, E., Perin, M., Colombo, A., Schuler, G., Barragan, P., Guagliumi, G., Molnar, F., and Falotico, R. (2002) A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. New. Engl. J. Med. 346, 1773-1780
94. Sakao, S., Tatsumi, K., and Voelkel, N. F. (2009) Endothelial cells and pulmonary arterial hypertension: apoptosis, proliferation, interaction and transdifferentiation. Resp. Res. 10, 95
95. Janes, M. R., Limon, J. J., So, L., Chen, J., Lim, R. J., Chavez, M. A., Vu, C., Lilly, M. B., Mallya, S., Ong, S. T., Konopleva, M., Martin, M. B., Ren, P., Liu, Y., Rommel, C., and Fruman, D. A. (2010) Effective and selective targeting of Leukemia cells using a TORC1/2 kinase inhibitor. Nat. Med. 16, 205-213
96. Hoang, B., Frost, P., Shi, Y., Belanger, E., Benavides, A., Pezeshkpour, G., Cappia, S., Guglielmelli, T., Gera, J., and Lichtenstein, A. (2010) Targeting TORC2 in multiple myeloma with a new mTOR kinase inhibitor. Blood 116, 4560-4568
97. Chresta, C. M., Davies, B. R., Hickson, I., Harding, T., Cosulich, S., Critchlow, S. E., Vincent, J. P., Ellston, R., Jones, D., Sini, P., James, D., Howard, Z., Dudley, P., Hughes, G., Smith, L., Maguire, S., Hummersone, M., Malagu, K., Menear, K., Jenkins, R., Jacobsen, M., Smith, G. C. M., Guichard, S., and Pass, M. (2010) AZD8055 is a potent, selective, and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity. Cancer Res. 70, 288-298
98. Engelman, J. A., Chen, L., Tan, X., Crosby, K., Guimaraes, A. R., Upadhyay, R., Maira, M., McNamara, K., Perera, S. A., Song, Y., Chirieac, L. R., Kaur, R., Lightbown, A., Simendinger, J., Li, T., Padera, R. F., Garcia-Echeverria, C., Weissleder, R., Mahmood, U., Cantley, L. C., and Wong, K. K. (2008) Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat. Med. 14, 1351-1356
99. Cho, D. C., Cohen, M. B., Panka, D. J., Collins, M., Ghebremichael, M., Atkins, M. B., Signoretti, S., and Mier, J. W. (2010) The efficacy of the novel dual PI3-kinase/mTOR inhibitor NVP-BEZ235 compared with rapamycin in renal cell carcinoma. Clin. Cancer Res. 16, 3628-3638
100. Serra, V., Markman, B., Scaltriti, M., Eichhorn, P. J. A., Valero, V., Guzman, M., Botero, M. L., Llonch, E., Atzori, F., Di Cosimo, S., Maira, M., Garcia, E. C., Parra, J. L., Arribas, J., and Baselga, J. (2008) NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer Res. 68, 8022-8030