HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ghanekar, A. Articles by Grant, D. R. Search for Related Content PubMed PubMed Citation Articles by Ghanekar, A. Articles by Grant, D. R. Pubmed/NCBI databases Gene GEO Profiles HomoloGene Protein UniGene Compound via MeSH Substance via MeSH Medline Plus Health Information Heart Transplantation

Endothelial Induction of fgl2 Contributes to Thrombosis during Acute Vascular Xenograft Rejection¹

Anand Ghanekar^2,*,,, Michael Mendicino^2,*,, Hao Liu^*,, Wei He^*, Mingfeng Liu^*,, Robert Zhong^||, M. James Phillips^¶, Gary A. Levy^*,, and David R. Grant^3,*,

^* Multi-Organ Transplant Program, Institute of Medical Science, and Departments of Surgery, Immunology, and ^¶ Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; and ^|| Multi-Organ Transplant Program, University of Western Ontario, London, Ontario, Canada

Thrombosis is a prominent feature of acute vascular rejection (AVR), the current barrier to survival of pig-to-primate xenografts. Fibrinogen-like protein 2 (fgl2/fibroleukin) is an inducible prothrombinase that plays an important role in the pathogenesis of fibrin deposition during viral hepatitis and cytokine-induced fetal loss. We hypothesized that induction of fgl2 on the vascular endothelium of xenografts contributes to thrombosis associated with AVR. We first examined fgl2 as a source of procoagulant activity in the pig-to-primate combination. The porcine fgl2 (pfgl2) was cloned and its chromosomal locus was identified. Recombinant pfgl2 protein expressed in vitro was detected on the cell surface and generated thrombin from human prothrombin. Studies of pig-to-baboon kidney xenografts undergoing AVR in vivo revealed induction of pfgl2 expression on graft vascular endothelial cells (ECs). Cultured porcine ECs activated by human TNF- in vitro demonstrated induction of pfgl2 expression and enhanced activation of human prothrombin. The availability of gene-targeted fgl2-deficient mice allowed the contribution of fgl2 to the pathogenesis of AVR to be directly examined in vivo. Hearts heterotopically transplanted from fgl2^+/+ and fgl2^+/– mice into Lewis rats developed AVR with intravascular thrombosis associated with induction of fgl2 in graft vascular ECs. In contrast, xenografts from fgl2^–/– mice were devoid of thrombosis. These observations collectively suggest that induction of fgl2 on the vascular endothelium plays a role in the pathogenesis of AVR-associated thrombosis. Manipulation of fgl2, in combination with other interventions, may yield novel strategies by which to overcome AVR and extend xenograft survival.

This article has been cited by other articles:

				I. Shalev, H. Liu, C. Koscik, A. Bartczak, M. Javadi, K. M. Wong, A. Maknojia, W. He, M. F. Liu, J. Diao, et al. Targeted Deletion of fgl2 Leads to Impaired Regulatory T Cell Activity and Development of Autoimmune Glomerulonephritis J. Immunol., January 1, 2008; 180(1): 249 - 260. [Abstract] [Full Text] [PDF]

				J. Mu, D. Qu, A. Bartczak, M. J. Phillips, J. Manuel, W. He, C. Koscik, M. Mendicino, L. Zhang, D. A. Clark, et al. Fgl2 deficiency causes neonatal death and cardiac dysfunction during embryonic and postnatal development in mice Physiol Genomics, September 11, 2007; 31(1): 53 - 62. [Abstract] [Full Text] [PDF]

				N. De Albuquerque, E. Baig, X. Ma, J. Zhang, W. He, A. Rowe, M. Habal, M. Liu, I. Shalev, G. P. Downey, et al. Murine hepatitis virus strain 1 produces a clinically relevant model of severe acute respiratory syndrome in a/j mice. J. Virol., November 1, 2006; 80(21): 10382 - 10394. [Abstract] [Full Text] [PDF]

				M. Mendicino, M. Liu, A. Ghanekar, W. He, C. Koscik, I. Shalev, M. Javadi, J. Turnbull, W. Chen, L. Fung, et al. Targeted Deletion of Fgl-2/Fibroleukin in the Donor Modulates Immunologic Response and Acute Vascular Rejection in Cardiac Xenografts Circulation, July 12, 2005; 112(2): 248 - 256. [Abstract] [Full Text] [PDF]

				Q. Ning, Y. Sun, M. Han, L. Zhang, C. Zhu, W. Zhang, H. Guo, J. Li, W. Yan, F. Gong, et al. Role of Fibrinogen-Like Protein 2 Prothrombinase/Fibroleukin in Experimental and Human Allograft Rejection J. Immunol., June 1, 2005; 174(11): 7403 - 7411. [Abstract] [Full Text] [PDF]

				N. Bardeesy, M. Kim, J. Xu, R.-S. Kim, Q. Shen, M. W. Bosenberg, W. H. Wong, and L. Chin Role of Epidermal Growth Factor Receptor Signaling in RAS-Driven Melanoma Mol. Cell. Biol., May 15, 2005; 25(10): 4176 - 4188. [Abstract] [Full Text] [PDF]