© 2000 American Heart Association, Inc.
Molecular Medicine |
Angiopoietin-1 Regulates Endothelial Cell Survival Through the Phosphatidylinositol 3'-Kinase/Akt Signal Transduction Pathway
From the National Creative Research Initiatives Center for Cardiac Regeneration and Institute of Cardiovascular Research (I.K., H.G.K., H.J.K., G.Y.K.), Department of Pathology (J.H.K.), Chonbuk National University School of Medicine, and Department of Biotechnology (J.-N.S.), Woosuk University, Chonju, Korea.
Correspondence to Gou Young Koh, MD, PhD, National Creative Research Initiatives Center for Cardiac Regeneration, Chonbuk National University School of Medicine, San 2-20, Keum-Am-Dong, Chonju, 560-180, Republic of Korea. E-mail gykoh{at}moak.chonbuk.ac.kr
Abstract—Angiopoietin-1 (Ang1) is a strong apoptosis survival factor for endothelial cells. In this study, the receptor/second messenger signal transduction pathway for the antiapoptotic effect of Ang1 on human umbilical vein endothelial cells was examined. Pretreatment with soluble Tie2 receptor, but not Tie1 receptor, blocked the Ang1-induced antiapoptotic effect. Ang1 induced phosphorylation of Tie2 and the p85 subunit of phosphatidylinositol 3'-kinase (PI 3'-kinase) and increased PI 3'-kinase activity in a dose-dependent manner. The PI 3'-kinase–specific inhibitors wortmannin and LY294002 blocked the Ang1-induced antiapoptotic effect. Ang1 induced phosphorylation of the serine-threonine kinase Akt at Ser473 in a PI 3'-kinase–dependent manner. Expression of a dominant-negative form of Akt reversed the Ang1-induced antiapoptotic effect. Ang1 mRNA and protein were present in vascular smooth muscle cells but not in endothelial cells. Cultured vascular smooth muscle cells, but not human umbilical vein endothelial cells, secreted Ang1. These findings indicate that the Tie2 receptor, PI 3'-kinase, and Akt are crucial elements in the signal transduction pathway leading to endothelial cell survival induced by the paracrine activity of Ang1.
Key Words: angiopoietin-1 • endothelial cell • apoptosis
This article has been cited by other articles:
 |
|
 |
|
  Q.-h. Tuo, H. Zeng, A. Stinnett, H. Yu, J. L. Aschner, D.-F. Liao, and J.-X. Chen Critical role of angiopoietins/Tie-2 in hyperglycemic exacerbation of myocardial infarction and impaired angiogenesis Am J Physiol Heart Circ Physiol, June 1, 2008; 294(6): H2547 - H2557. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. M. de Resende and A. S. Greene Effect of ANG II on endothelial cell apoptosis and survival and its impact on skeletal muscle angiogenesis after electrical stimulation Am J Physiol Heart Circ Physiol, June 1, 2008; 294(6): H2814 - H2821. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Cai, O. Kehoe, G. M. Smith, P. Hykin, and M. E. Boulton The Angiopoietin/Tie-2 System Regulates Pericyte Survival and Recruitment in Diabetic Retinopathy Invest. Ophthalmol. Vis. Sci., May 1, 2008; 49(5): 2163 - 2171. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Maliba, A. Brkovic, P.-E. Neagoe, L. R. Villeneuve, and M. G. Sirois Angiopoietin-mediated endothelial P-selectin translocation: cell signaling mechanisms J. Leukoc. Biol., February 1, 2008; 83(2): 352 - 360. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Rao, I. B. Lobov, J. E. Vallance, K. Tsujikawa, I. Shiojima, S. Akunuru, K. Walsh, L. E. Benjamin, and R. A. Lang Obligatory participation of macrophages in an angiopoietin 2-mediated cell death switch Development, December 15, 2007; 134(24): 4449 - 4458. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. B. Marron, H. Singh, T. A. Tahir, J. Kavumkal, H.-Z. Kim, G. Y. Koh, and N. P. J. Brindle Regulated Proteolytic Processing of Tie1 Modulates Ligand Responsiveness of the Receptor-tyrosine Kinase Tie2 J. Biol. Chem., October 19, 2007; 282(42): 30509 - 30517. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. T. Yuan, S. Venkatesha, B. Chan, U. Deutsch, T. Mammoto, V. P. Sukhatme, A. S. Woolf, and S. A. Karumanchi Activation of the orphan endothelial receptor Tie1 modifies Tie2-mediated intracellular signaling and cell survival FASEB J, October 1, 2007; 21(12): 3171 - 3183. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Hur, C.-H. Yoon, C.-S. Lee, T.-Y. Kim, I.-y. Oh, K.-W. Park, J.-H. Kim, H.-S. Lee, H.-J. Kang, I.-H. Chae, et al. Akt Is a Key Modulator of Endothelial Progenitor Cell Trafficking in Ischemic Muscle Stem Cells, July 1, 2007; 25(7): 1769 - 1778. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Brkovic, M. Pelletier, D. Girard, and M. G. Sirois Angiopoietin chemotactic activities on neutrophils are regulated by PI-3K activation J. Leukoc. Biol., April 1, 2007; 81(4): 1093 - 1101. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. M. Black, J. F. Grehan, A. L. Rivard, B. A. Benson, A. E. Wahner, A. E. Koch, B. K. Levay-Young, and A. P. Dalmasso Porcine Endothelial Cells and Iliac Arteries Transduced with AdenoIL-4 Are Intrinsically Protected, through Akt Activation, against Immediate Injury Caused by Human Complement J. Immunol., November 15, 2006; 177(10): 7355 - 7363. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Daly, E. Pasnikowski, E. Burova, V. Wong, T. H. Aldrich, J. Griffiths, E. Ioffe, T. J. Daly, J. P. Fandl, N. Papadopoulos, et al. Angiopoietin-2 functions as an autocrine protective factor in stressed endothelial cells PNAS, October 17, 2006; 103(42): 15491 - 15496. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-X. Chen, H. Zeng, M. L Lawrence, T. S. Blackwell, and B. Meyrick Angiopoietin-1-induced angiogenesis is modulated by endothelial NADPH oxidase Am J Physiol Heart Circ Physiol, October 1, 2006; 291(4): H1563 - H1572. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Jiang, H. Kh. Haider, N. M. Idris, A. Salim, and M. Ashraf Supportive Interaction Between Cell Survival Signaling and Angiocompetent Factors Enhances Donor Cell Survival and Promotes Angiomyogenesis for Cardiac Repair Circ. Res., September 29, 2006; 99(7): 776 - 784. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Bogdanovic, V. P. K. H. Nguyen, and D. J. Dumont Activation of Tie2 by angiopoietin-1 and angiopoietin-2 results in their release and receptor internalization J. Cell Sci., September 1, 2006; 119(17): 3551 - 3560. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Kim, S.-O. Moon, S. Y. Lee, K. Y. Jang, C.-H. Cho, G. Y. Koh, K.-S. Choi, K.-H. Yoon, M. J. Sung, D. H. Kim, et al. COMP-Angiopoietin-1 Ameliorates Renal Fibrosis in a Unilateral Ureteral Obstruction Model J. Am. Soc. Nephrol., September 1, 2006; 17(9): 2474 - 2483. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Kobayashi, L. M. DeBusk, Y. O. Babichev, D. J. Dumont, and P. C. Lin Hepatocyte growth factor mediates angiopoietin-induced smooth muscle cell recruitment Blood, August 15, 2006; 108(4): 1260 - 1266. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. D. Balsara, F. J. Castellino, and V. A. Ploplis A Novel Function of Plasminogen Activator Inhibitor-1 in Modulation of the AKT Pathway in Wild-type and Plasminogen Activator Inhibitor-1-deficient Endothelial Cells J. Biol. Chem., August 11, 2006; 281(32): 22527 - 22536. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Kobayashi, T. Kondo, N. Inoue, M. Aoki, M. Mizuno, K. Komori, J. Yoshida, and T. Murohara Combination of In Vivo Angiopoietin-1 Gene Transfer and Autologous Bone Marrow Cell Implantation for Functional Therapeutic Angiogenesis Arterioscler. Thromb. Vasc. Biol., July 1, 2006; 26(7): 1465 - 1472. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. M. Kim, K. E. Kim, G. Y. Koh, Y.-S. Ho, and K.-J. Lee Hydrogen peroxide produced by angiopoietin-1 mediates angiogenesis. Cancer Res., June 15, 2006; 66(12): 6167 - 6174. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. I. Nykanen, K. Pajusola, R. Krebs, M. A.I. Keranen, O. Raisky, P. K. Koskinen, K. Alitalo, and K. B. Lemstrom Common Protective and Diverse Smooth Muscle Cell Effects of AAV-Mediated Angiopoietin-1 and -2 Expression in Rat Cardiac Allograft Vasculopathy Circ. Res., June 9, 2006; 98(11): 1373 - 1380. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. P.J. Brindle, P. Saharinen, and K. Alitalo Signaling and Functions of Angiopoietin-1 in Vascular Protection Circ. Res., April 28, 2006; 98(8): 1014 - 1023. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Nishiyama, K. Takaji, K. Kataoka, Y. Kurihara, M. Yoshimura, A. Kato, H. Ogawa, and H. Kurihara Id1 Gene Transfer Confers Angiogenic Property on Fully Differentiated Endothelial Cells and Contributes to Therapeutic Angiogenesis Circulation, November 1, 2005; 112(18): 2840 - 2850. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Cascone, L. Napione, F. Maniero, G. Serini, and F. Bussolino Stable interaction between {alpha}5{beta}1 integrin and Tie2 tyrosine kinase receptor regulates endothelial cell response to Ang-1 J. Cell Biol., September 12, 2005; 170(6): 993 - 1004. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Murakami, H. Takagi, K. Suzuma, I. Suzuma, H. Ohashi, D. Watanabe, T. Ojima, E. Suganami, M. Kurimoto, H. Kaneto, et al. Angiopoietin-1 Attenuates H2O2-induced SEK1/JNK Phosphorylation through the Phosphatidylinositol 3-Kinase/Akt Pathway in Vascular Endothelial Cells J. Biol. Chem., September 9, 2005; 280(36): 31841 - 31849. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Kanda, Y. Miyata, Y. Mochizuki, T. Matsuyama, and H. Kanetake Angiopoietin 1 Is Mitogenic for Cultured Endothelial Cells Cancer Res., August 1, 2005; 65(15): 6820 - 6827. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. F. Grehan, B. K. Levay-Young, J. L. Fogelson, V. Francois-Bongarcon, B. A. Benson, and A. P. Dalmasso IL-4 and IL-13 Induce Protection of Porcine Endothelial Cells from Killing by Human Complement and from Apoptosis through Activation of a Phosphatidylinositide 3-Kinase/Akt Pathway J. Immunol., August 1, 2005; 175(3): 1903 - 1910. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J S Mohan, P L Lip, A D Blann, D Bareford, and G Y H Lip The angiopoietin/Tie-2 system in proliferative sickle retinopathy: relation to vascular endothelial growth factor, its soluble receptor Flt-1 and von Willebrand factor, and to the effects of laser treatment Br. J. Ophthalmol., July 1, 2005; 89(7): 815 - 819. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Tammela, A. Saaristo, M. Lohela, T. Morisada, J. Tornberg, C. Norrmen, Y. Oike, K. Pajusola, G. Thurston, T. Suda, et al. Angiopoietin-1 promotes lymphatic sprouting and hyperplasia Blood, June 15, 2005; 105(12): 4642 - 4648. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Morisada, Y. Oike, Y. Yamada, T. Urano, M. Akao, Y. Kubota, H. Maekawa, Y. Kimura, M. Ohmura, T. Miyamoto, et al. Angiopoietin-1 promotes LYVE-1-positive lymphatic vessel formation Blood, June 15, 2005; 105(12): 4649 - 4656. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. C. Weber, H. Cai, M. Ehrbar, H. Kubota, G. Martiny-Baron, W. Weber, V. Djonov, E. Weber, A. S. Mallik, M. Fussenegger, et al. Effects of Protein and Gene Transfer of the Angiopoietin-1 Fibrinogen-like Receptor-binding Domain on Endothelial and Vessel Organization J. Biol. Chem., June 10, 2005; 280(23): 22445 - 22453. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K.-T. Kim, H.-H. Choi, M. O. Steinmetz, B. Maco, R. A. Kammerer, S. Y. Ahn, H.-Z. Kim, G. M. Lee, and G. Y. Koh Oligomerization and Multimerization Are Critical for Angiopoietin-1 to Bind and Phosphorylate Tie2 J. Biol. Chem., May 20, 2005; 280(20): 20126 - 20131. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Lelievre, P.-M. Bourbon, L.-J. Duan, R. L. Nussbaum, and G.-H. Fong Deficiency in the p110{alpha} subunit of PI3K results in diminished Tie2 expression and Tie2-/--like vascular defects in mice Blood, May 15, 2005; 105(10): 3935 - 3938. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J I Patel, P G Hykin, Z J Gregor, M Boulton, and I A Cree Angiopoietin concentrations in diabetic retinopathy Br. J. Ophthalmol., April 1, 2005; 89(4): 480 - 483. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. Dallabrida, N. Ismail, J. R. Oberle, B. E. Himes, and M. A. Rupnick Angiopoietin-1 Promotes Cardiac and Skeletal Myocyte Survival Through Integrins Circ. Res., March 4, 2005; 96(4): e8 - e24. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Voskas, N. Jones, P. Van Slyke, C. Sturk, W. Chang, A. Haninec, Y. O. Babichev, J. Tran, Z. Master, S. Chen, et al. A Cyclosporine-Sensitive Psoriasis-Like Disease Produced in Tie2 Transgenic Mice Am. J. Pathol., March 1, 2005; 166(3): 843 - 855. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Kido, L. Du, C. C. Sullivan, R. Deutsch, S. W. Jamieson, and P. A. Thistlethwaite Gene transfer of a TIE2 receptor antagonist prevents pulmonary hypertension in rodents J. Thorac. Cardiovasc. Surg., February 1, 2005; 129(2): 268 - 276. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. F. Sun, T. Phung, I. Shiojima, T. Felske, J. N. Upalakalin, D. Feng, T. Kornaga, T. Dor, A. M. Dvorak, K. Walsh, et al. Microvascular patterning is controlled by fine-tuning the Akt signal PNAS, January 4, 2005; 102(1): 128 - 133. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Witzenbichler, D. Westermann, S. Knueppel, H.-P. Schultheiss, and C. Tschope Protective Role of Angiopoietin-1 in Endotoxic Shock Circulation, January 4, 2005; 111(1): 97 - 105. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Md. R. Abid, I. G. Schoots, K. C. Spokes, S.-Q. Wu, C. Mawhinney, and W. C. Aird Vascular Endothelial Growth Factor-mediated Induction of Manganese Superoxide Dismutase Occurs through Redox-dependent Regulation of Forkhead and I{kappa}B/NF-{kappa}B J. Biol. Chem., October 15, 2004; 279(42): 44030 - 44038. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Xu, Y.-j. Liu, and Q. Yu Angiopoietin-3 Is Tethered on the Cell Surface via Heparan Sulfate Proteoglycans J. Biol. Chem., September 24, 2004; 279(39): 41179 - 41188. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Xu, Y.-j. Liu, and Q. Yu Angiopoietin-3 Inhibits Pulmonary Metastasis by Inhibiting Tumor Angiogenesis Cancer Res., September 1, 2004; 64(17): 6119 - 6126. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. J. LEE, C.-H. CHO, S.-J. HWANG, H.-H. CHOI, K.-T. KIM, S. Y. AHN, J.-H. KIM, J.-L. OH, G. M. LEE, and G. Y. KOH Biological characterization of angiopoietin-3 and angiopoietin-4 FASEB J, August 1, 2004; 18(11): 1200 - 1208. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-X. Chen, Y. Chen, L. DeBusk, W. Lin, and P. C. Lin Dual functional roles of Tie-2/angiopoietin in TNF-{alpha}-mediated angiogenesis Am J Physiol Heart Circ Physiol, July 1, 2004; 287(1): H187 - H195. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. N. Carr, M. G. Davis, E. Eby-Wilkens, B. W. Howard, B. A. Towne, T. E. Dufresne, and K. G. Peters Tyrosine phosphatase inhibition augments collateral blood flow in a rat model of peripheral vascular disease Am J Physiol Heart Circ Physiol, July 1, 2004; 287(1): H268 - H276. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Daly, V. Wong, E. Burova, Y. Wei, S. Zabski, J. Griffiths, K.-M. Lai, H. C. Lin, E. Ioffe, G. D. Yancopoulos, et al. Angiopoietin-1 modulates endothelial cell function and gene expression via the transcription factor FKHR (FOXO1) Genes & Dev., May 1, 2004; 18(9): 1060 - 1071. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Y. Ahn, C.-H. Cho, K.-G. Park, H. J. Lee, S. Lee, S. K. Park, I.-K. Lee, and G. Y. Koh Tumor Necrosis Factor-{alpha} Induces Fractalkine Expression Preferentially in Arterial Endothelial Cells and Mithramycin A Suppresses TNF-{alpha}-Induced Fractalkine Expression Am. J. Pathol., May 1, 2004; 164(5): 1663 - 1672. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-H. Cho, C. S. Lee, M. Chang, I.-H. Jang, S. J. Kim, I. Hwang, S. H. Ryu, C. O. Lee, and G. Y. Koh Localization of VEGFR-2 and PLD2 in endothelial caveolae is involved in VEGF-induced phosphorylation of MEK and ERK Am J Physiol Heart Circ Physiol, May 1, 2004; 286(5): H1881 - H1888. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-H. Cho, R. A. Kammerer, H. J. Lee, M. O. Steinmetz, Y. S. Ryu, S. H. Lee, K. Yasunaga, K.-T. Kim, I. Kim, H.-H. Choi, et al. COMP-Ang1: A designed angiopoietin-1 variant with nonleaky angiogenic activity PNAS, April 13, 2004; 101(15): 5547 - 5552. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-H. Cho, R. A. Kammerer, H. J. Lee, K. Yasunaga, K.-T. Kim, H.-H. Choi, W. Kim, S. H. Kim, S. K. Park, G. M. Lee, et al. Designed angiopoietin-1 variant, COMP-Ang1, protects against radiation-induced endothelial cell apoptosis PNAS, April 13, 2004; 101(15): 5553 - 5558. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Ohashi, H. Takagi, H. Oh, K. Suzuma, I. Suzuma, N. Miyamoto, A. Uemura, D. Watanabe, T. Murakami, T. Sugaya, et al. Phosphatidylinositol 3-Kinase/Akt Regulates Angiotensin II-Induced Inhibition of Apoptosis in Microvascular Endothelial Cells by Governing Survivin Expression and Suppression of Caspase-3 Activity Circ. Res., April 2, 2004; 94(6): 785 - 793. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Y. Chong, G. J. Caine, B. Freestone, A. D. Blann, and G. Y. H. Lip Plasma angiopoietin-1, angiopoietin-2, and angiopoietin receptor tie-2 levels in congestive heart failure J. Am. Coll. Cardiol., February 4, 2004; 43(3): 423 - 428. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-x. Chen, M. L. Lawrence, G. Cunningham, B. W. Christman, and B. Meyrick HSP90 and Akt modulate Ang-1-induced angiogenesis via NO in coronary artery endothelium J Appl Physiol, February 1, 2004; 96(2): 612 - 620. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Zadeh, B. Qian, A. Okhowat, N. Sabha, C. D. Kontos, and A. Guha Targeting the Tie2/Tek Receptor in Astrocytomas Am. J. Pathol., February 1, 2004; 164(2): 467 - 476. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Ouchi, H. Kobayashi, S. Kihara, M. Kumada, K. Sato, T. Inoue, T. Funahashi, and K. Walsh Adiponectin Stimulates Angiogenesis by Promoting Cross-talk between AMP-activated Protein Kinase and Akt Signaling in Endothelial Cells J. Biol. Chem., January 9, 2004; 279(2): 1304 - 1309. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. G. Peters, C. D. Kontos, P. C. Lin, A. L. Wong, P. Rao, L. Huang, M. W. Dewhirst, and S. Sankar Functional Significance of Tie2 Signaling in the Adult Vasculature Recent Prog. Horm. Res., January 1, 2004; 59(1): 51 - 71. [Abstract] [Full Text]
|
|
|
|
|
|
A. Tadros, D. P. Hughes, B. J. Dunmore, and N. P. J. Brindle ABIN-2 protects endothelial cells from death and has a role in the antiapoptotic effect of angiopoietin-1 Blood, December 15, 2003; 102(13): 4407 - 4409. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Adini, I. Rabinovitz, J. F. Sun, G. C. Prendergast, and |