Published online before print December 20, 2004, doi: 10.1161/01.CIR.0000151287.08202.8E
(Circulation. 2005;111:97-105.)
© 2005 American Heart Association, Inc.
Vascular Medicine |
Protective Role of Angiopoietin-1 in Endotoxic Shock
From the Department of Cardiology and Pneumology, Universitätsmedizin Berlin, Charité Campus Benjamin Franklin, Berlin, Germany.
Correspondence to Bernhard Witzenbichler, MD, Department of Cardiology and Pneumology, Universitätsmedizin Berlin, Charité Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany. E-mail b.witzenbichler{at}gmx.de
Received April 26, 2004; revision received September 1, 2004; accepted September 24, 2004.
Background— Angiopoietin-1 (Ang1) plays an essential role in embryonic vasculature development, protects the adult peripheral vasculature from leakage, and has antiinflammatory properties. Because endotoxin-induced shock is a condition with microvascular leakage resulting from inflammation, we examined the potential therapeutic benefit of Ang1 in a murine model of lipopolysaccharide (LPS)-induced endotoxic shock.
Methods and Results— To induce endotoxic shock, LPS was injected intraperitoneally into C57BL/6 mice. Half of the mice received an intravenous application of 1.0x109 plaque-forming units of an adenoviral construct expressing human Ang1 (AdhAng1); in the other half an identical vector expressing green fluorescent protein (AdGFP) was injected as a control. In the AdhAng1-treated mice, hepatic transfection and high expression of circulating Ang1 protein were observed. Whereas in LPS-treated control mice, hemodynamic function was severely depressed 12 hours after LPS injection (decrease of blood pressure from 91±3 to 49±7 mm Hg, dP/dtmax from 7284±550 to 2699±233 mm Hg/s, cardiac output from 11.3±1.2 to 2.8±0.8 mL/min; P<0.0005), in LPS-treated AdhAng1 mice blood pressure fell only to 76±3 mm Hg, dP/dtmax to 5091±489 mm Hg/s, and cardiac output to 6.7±1.4 mL/min (P<0.05). This resistance to LPS-induced hemodynamic changes was reflected by an improved Kaplan-Meier survival rate of the AdhAng1 mice. Histological analysis revealed that lung injury after LPS injection was markedly attenuated in AdhAng1 mice. In addition, LPS-induced increase in lung water content and pulmonary myeloperoxidase activity was significantly reduced. Furthermore, LPS-induced increases in the expression level of vascular cell adhesion molecule-1, intracellular adhesion molecule-1, and E-selectin protein in the lungs were markedly lower in AdhAng1 mice than in control mice. Finally, in the mice overexpressing Ang1, pulmonary endothelial NO synthase (eNOS) expression and activity remained preserved after LPS challenge, providing evidence that the beneficial effect of Ang1 in endotoxic shock is mediated by eNOS-derived NO.
Conclusions— Our study demonstrates an improved mortality rate in mice with endotoxic shock pretreated with an adenoviral construct encoding Ang1. The enhanced survival rate induced by Ang1 was accompanied by an improvement in hemodynamic function, reduced lung injury, a lower expression of inflammatory adhesion molecules, and preserved eNOS activity in the lung tissue. Ang1 may therefore have utility as an adjunctive agent for the treatment of septic shock condition.
Key Words: shock • genes • cell adhesion molecules • lung • angiogenesis
Related Article:
Circulation 2005 111: 2-4.
This article has been cited by other articles:
 |
|
 |
|
  D. C. M. Simoes, T. Vassilakopoulos, D. Toumpanakis, K. Petrochilou, C. Roussos, and A. Papapetropoulos Angiopoietin-1 Protects against Airway Inflammation and Hyperreactivity in Asthma Am. J. Respir. Crit. Care Med., June 15, 2008; 177(12): 1314 - 1321. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Mammoto, S. M. Parikh, A. Mammoto, D. Gallagher, B. Chan, G. Mostoslavsky, D. E. Ingber, and V. P. Sukhatme Angiopoietin-1 Requires p190 RhoGAP to Protect against Vascular Leakage in Vivo J. Biol. Chem., August 17, 2007; 282(33): 23910 - 23918. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. S. Williams, R. Issa, S. Y. Leung, P. Nath, G. D. Ferguson, B. L. Bennett, I. M. Adcock, and K. F. Chung Attenuation of Ozone-Induced Airway Inflammation and Hyper-Responsiveness by c-Jun NH2 Terminal Kinase Inhibitor SP600125 J. Pharmacol. Exp. Ther., July 1, 2007; 322(1): 351 - 359. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. D. McCarter, S. H. J. Mei, P. F. H. Lai, Q. W. Zhang, C. H. Parker, R. S. Suen, R. D. Hood, Y. D. Zhao, Y. Deng, R. N. N. Han, et al. Cell-based Angiopoietin-1 Gene Therapy for Acute Lung Injury Am. J. Respir. Crit. Care Med., May 15, 2007; 175(10): 1014 - 1026. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Pfaff, U. Fiedler, and H. G. Augustin Emerging roles of the Angiopoietin-Tie and the ephrin-Eph systems as regulators of cell trafficking J. Leukoc. Biol., October 1, 2006; 80(4): 719 - 726. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. S.M., M. T., S. A., Y. H.T., C. D., K. S.A., S. V.P., W. B., L. P.S., T. S.M., et al. Leaking Capillaries and White Lung in Sepsis--Is Angiopoietin 2 the Culprit?: Excess Circulating Angiopoietin-2 May Contribute to Pulmonary Vascular Leak in Sepsis in Humans. PLoS Medicine 3: e46, 2006 J. Am. Soc. Nephrol., May 1, 2006; 17(5): 1207 - 1217. [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]
|
|
|
|
 |
|
 F. Baffert, T. Le, G. Thurston, and D. M. McDonald Angiopoietin-1 decreases plasma leakage by reducing number and size of endothelial gaps in venules Am J Physiol Heart Circ Physiol, January 1, 2006; 290(1): H107 - H118. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. W. Gilroy and P. Vallance Resolution for Sepsis? Circulation, January 4, 2005; 111(1): 2 - 4. [Full Text] [PDF]
|
|