Atherogenesis may be conceptualized as a response to vascular cell injury or stress. The endothelium constitutes a thromboresistant surface that is intimately associated with flowing blood. However, perturbation of the endothelial cell by any of several stimuli confers a more prothrombotic, adhesive phenotype that predisposes to influx of cellular elements, release of mitogens, and lipid accumulation. We recently identified the calcium-regulated phospholipid-binding protein, annexin II, as an endothelial cell surface receptor for two fibrinolytic proteins, plasminogen and tissue plasminogen activator. Since annexin II appears to possess distinct binding domains for these two ligands, we have hypothesized that it mediates their assembly as well as generation of the multi-functional serine protease, plasmin. Our further studies have shown that purified native annexin II enhances the catalytic efficiency of t-PA- dependent plasminogen activation by 60-fold. Although several studies have demonstrated the presence of annexin II on endothelial cells, and other cells, the mechanism by which it is translocated to the cell surface is unknown since it lacks a typical hydrophobic signal sequence. Our preliminary data suggest that annexin II translocation is a slow process in resting cells, but that it is significantly more rapid in response to specific forms of cellular """"""""stress"""""""" such as heat shock or viral infection. Additional studies indicate that full-length annexin II must be proteolytically modified before it can function fully as fibrinolytic receptor, and that urokinase and t-PA represent candidate annexin II activators.
The specific aims of this proposal are to (1) determine the mechanism by which the endothelial cell translocates annexin II to the cell surface under resting conditions, (2) identify modifications of this process that occur in response to cellular injury or stress, and (3) delineate the mechanism by which annexin II is activated to become a fully functional catalytic receptor. The success of the proposed studies will depend upon critical interactions with other members of the Program Project. Specifically, Dr. Roy Silverstein will assist in preparation of stably transfected 293 cell lines, and Dr. Suman F. A. Pearce will conduct structural analyses of mutant annexins. Drs. David Hajjar and Robert Kaner will collaborate on studies involving processing of annexin II in the setting of virus-induced stress. We hypothesize that transport and processing of annexin II may be significantly perturbed under conditions that lead to cellular proliferation and lipid accumulation, the hallmarks of atherosclerosis.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Weill Medical College of Cornell University
New York
United States
Zip Code
Ramakrishnan, Devi Prasadh; Hajj-Ali, Rula A; Chen, Yiliang et al. (2016) Extracellular Vesicles Activate a CD36-Dependent Signaling Pathway to Inhibit Microvascular Endothelial Cell Migration and Tube Formation. Arterioscler Thromb Vasc Biol 36:534-44
Hajjar, Katherine A (2015) The Biology of Annexin A2: From Vascular Fibrinolysis to Innate Immunity. Trans Am Clin Climatol Assoc 126:144-55
Dassah, Maryann; Almeida, Dena; Hahn, Rebecca et al. (2014) Annexin A2 mediates secretion of collagen VI, pulmonary elasticity and apoptosis of bronchial epithelial cells. J Cell Sci 127:828-44
Anastasia, Agustin; Deinhardt, Katrin; Wang, Shiyang et al. (2014) Trkb signaling in pericytes is required for cardiac microvessel stabilization. PLoS One 9:e87406
Abbott, Geoffrey W; Tai, Kwok-Keung; Neverisky, Daniel L et al. (2014) KCNQ1, KCNE2, and Na+-coupled solute transporters form reciprocally regulating complexes that affect neuronal excitability. Sci Signal 7:ra22
Hajjar, David P; Gotto Jr, Antonio M (2013) Biological relevance of inflammation and oxidative stress in the pathogenesis of arterial diseases. Am J Pathol 182:1474-81
Kennedy, David J; Chen, Yiliang; Huang, Wenxin et al. (2013) CD36 and Na/K-ATPase-?1 form a proinflammatory signaling loop in kidney. Hypertension 61:216-24
Zhou, Ming-Sheng; Chadipiralla, Kiranmai; Mendez, Armando J et al. (2013) Nicotine potentiates proatherogenic effects of oxLDL by stimulating and upregulating macrophage CD36 signaling. Am J Physiol Heart Circ Physiol 305:H563-74
Luo, Min; Hajjar, Katherine A (2013) Annexin A2 system in human biology: cell surface and beyond. Semin Thromb Hemost 39:338-46
Siao, Chia-Jen; Lorentz, Christina U; Kermani, Pouneh et al. (2012) ProNGF, a cytokine induced after myocardial infarction in humans, targets pericytes to promote microvascular damage and activation. J Exp Med 209:2291-305

Showing the most recent 10 out of 226 publications