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Blood, 1 June 2007, Vol. 109, No. 11, pp. 4793-4802. Prepublished online as a Blood First Edition Paper on February 1, 2007; DOI 10.1182/blood-2006-11-059352. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2006-11-059352v1 109/11/4793    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Nguyen, T. M. B. Articles by Ramakrishnan, S. Search for Related Content PubMed PubMed Citation Articles by Nguyen, T. M. B. Articles by Ramakrishnan, S. Related Collections Hemostasis, Thrombosis, and Vascular Biology Apoptosis Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Kringle 5 of human plasminogen, an angiogenesis inhibitor, induces both autophagy and apoptotic death in endothelial cells Tri Minh Bui Nguyen1, Indira V. Subramanian2, Ameeta Kelekar3, and Sundaram Ramakrishnan1,2 1 Department of Pharmacology, University of Minnesota, Minneapolis; 2 Department of Obstetrics and Gynecology and Women's Health, University of Minnesota, Minneapolis; 3 Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis Inhibition of endothelial cell proliferation and angiogenesis is emerging as an important strategy in cancer therapeutics. Kringle 5 (K5) of human plasminogen is a potent angiogenesis inhibitor. Previous studies have shown K5 exposure promotes caspase activity and apoptosis in endothelial cells. Here we report that K5 treatment evokes an autophagic response in endothelial cells that is specific and initiated even in the absence of nutritional stress. Endothelial cells exposed to K5 up-regulated Beclin 1 levels within a few hours. Furthermore, progressively increasing amounts of antiapoptotic Bcl-2 were found to be complexed with Beclin 1, although total levels of Bcl-2 remained unchanged. Prolonged exposure to K5 ultimately led to apoptosis via mitochondrial membrane depolarization and caspase activation in endothelial cells. Knocking down Beclin 1 levels by RNA interference decreased K5 induced autophagy but accelerated K5-induced apoptosis. These studies suggest that interfering with the autophagic survival response can potentiate the antiangiogenic effects of Kringle 5 in endothelial cells. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: B. C. McFarland, J. Stewart Jr., A. Hamza, R. Nordal, D. J. Davidson, J. Henkin, and C. L. Gladson Plasminogen Kringle 5 Induces Apoptosis of Brain Microvessel Endothelial Cells: Sensitization by Radiation and Requirement for GRP78 and LRP1 Cancer Res., July 1, 2009; 69(13): 5537 - 5545. [Abstract] [Full Text] [PDF] V. L. M. Herrera, J. L. Decano, P. Bagamasbad, T. Kufahl, M. Steffen, and N. Ruiz-Opazo Sex-specific hippocampus-dependent cognitive deficits and increased neuronal autophagy in DEspR haploinsufficiency in mice Physiol Genomics, November 12, 2008; 35(3): 316 - 329. [Abstract] [Full Text] [PDF]

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