Annexin A2 in Fibrinolysis, Inflammation and Fibrosis

As a cell surface tissue plasminogen activator (tPA)-plasminogen receptor, the annexin A2 (A2) complex facilitates plasmin generation on the endothelial cell surface, and is an established regulator of hemostasis. Whereas A2 is overexpressed in hemorrhagic disease such as acute promyelocytic leukemia, its underexpression or impairment may result in thrombosis, as in antiphospholipid syndrome, venous thromboembolism, or atherosclerosis. Within immune response cells, A2 orchestrates membrane repair, vesicle fusion, and cytoskeletal organization, thus playing a critical role in inflammatory response and tissue injury. Dysregulation of A2 is evident in multiple human disorders, and may contribute to the pathogenesis of various inflammatory disorders. The fibrinolytic system, moreover, is central to wound healing through its ability to remodel the provisional matrix and promote angiogenesis. A2 dysfunction may also promote tissue fibrogenesis and end-organ fibrosis.

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EPAC1 regulates endothelial Annexin A2 cell surface translocation and plasminogen activation

10.1101/187559 ◽

2017 ◽

Author(s):

Wenli Yang ◽

Fang C. Mei ◽

Xiaodong Cheng

Keyword(s):

Endothelial Cells ◽

Cell Surface ◽

Critical Role ◽

Annexin A2 ◽

Plasminogen Activation ◽

Endothelial Cell Surface ◽

Cellular Processes ◽

Wide Range ◽

Tissue Plasminogen ◽

Surface Translocation

ABSTRACTAnnexins, a family of highly conserved calcium-and phospholipid-binding proteins, play important roles in a wide range of physiological functions. Among the twelve known annexins in human, Annexin A2 (AnxA2) is one of the most extensively studied and has been implicated in various human diseases. AnxA2 can exist as a monomer or a heterotetrameric complex with S100A10 (P11) and plays a critical role in many cellular processes including exocytosis/endocytosis and membrane organization. At the endothelial cell surface, (AnxA2•P11)2 tetramer, acting as a coreceptor for plasminogen and tissue plasminogen activator (t-PA), accelerates t-PA dependent activation of the fibrinolytic protease, plasmin, the enzyme responsible for thrombus dissolution and degradation of fibrin. This study shows that exchange proteins directly activated by cAMP isoform 1 (EPAC1) interacts with AnxA2 and regulates its biological functions by modulating its membrane translocation in endothelial cells. Using genetic and pharmacological approaches, it is demonstrated that EPAC1, acting through the PLCε-PKC pathway, inhibits AnxA2 surface translocation and plasminogen activation. These results suggest that EPAC1 plays a role in the regulation of fibrinolysis in endothelial cells and may represent a novel therapeutic target for disorders of fibrinolysis.

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The Annexin A2/S100A10 System in Health and Disease: Emerging Paradigms

Journal of Biomedicine and Biotechnology ◽

10.1155/2012/406273 ◽

2012 ◽

Vol 2012 ◽

pp. 1-13 ◽

Cited By ~ 45

Author(s):

Nadia Hedhli ◽

Domenick J. Falcone ◽

Bihui Huang ◽

Gabriela Cesarman-Maus ◽

Rosemary Kraemer ◽

...

Keyword(s):

Serotonin Receptor ◽

Human Cancer ◽

High Titer ◽

Critical Role ◽

Annexin A2 ◽

Avascular Osteonecrosis ◽

Kinase Substrate ◽

New Findings ◽

Human Disorders ◽

Associated Proteins

Since its discovery as a src kinase substrate more than three decades ago, appreciation for the physiologic functions of annexin A2 and its associated proteins has increased dramatically. With its binding partner S100A10 (p11), A2 forms a cell surface complex that regulates generation of the primary fibrinolytic protease, plasmin, and is dynamically regulated in settings of hemostasis and thrombosis. In addition, the complex is transcriptionally upregulated in hypoxia and promotes pathologic neoangiogenesis in the tissues such as the retina. Dysregulation of both A2 and p11 has been reported in examples of rodent and human cancer. Intracellularly, A2 plays a critical role in endosomal repair in postarthroplastic osteolysis, and intracellular p11 regulates serotonin receptor activity in psychiatric mood disorders. In human studies, the A2 system contributes to the coagulopathy of acute promyelocytic leukemia, and is a target of high-titer autoantibodies in patients with antiphospholipid syndrome, cerebral thrombosis, and possibly preeclampsia. Polymorphisms in the humanANXA2gene have been associated with stroke and avascular osteonecrosis of bone, two severe complications of sickle cell disease. Together, these new findings suggest that manipulation of the annexin A2/S100A10 system may offer promising new avenues for treatment of a spectrum of human disorders.

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Dysfunction of annexin A2 contributes to hyperglycaemia-induced loss of human endothelial cell surface fibrinolytic activity

Thrombosis and Haemostasis ◽

10.1160/th12-12-0944 ◽

2013 ◽

Vol 109 (06) ◽

pp. 1070-1078 ◽

Cited By ~ 16

Author(s):

Zhanyang Yu ◽

Xiang Fan ◽

Ning Liu ◽

Min Yan ◽

Zhong Chen ◽

...

Keyword(s):

Endothelial Cells ◽

Endothelial Cell ◽

Cell Surface ◽

Protein Expression ◽

Plasminogen Activator ◽

Fibrinolytic Activity ◽

Annexin A2 ◽

Tissue Type ◽

Endothelial Cell Surface ◽

Pai 1

SummaryHyperglycaemia impairs fibrinolytic activity on the surface of endothelial cells, but the underlying mechanisms are not fully understood. In this study, we tested the hypothesis that hyperglycaemia causes dysfunction of the endothelial membrane protein annexin A2, thereby leading to an overall reduction of fibrinolytic activity. Hyperglycaemia for 7 days significantly reduced cell surface fibrinolytic activity in human brain microvascular endothelial cells (HBMEC). Hyperglycaemia also decreased tissue type plasminogen activator (t-PA), plasminogen, and annexin A2 mRNA and protein expression, while increasing plasminogen activator inhibitor-1 (PAI-1). No changes in p11 mRNA or protein expression were detected. Hyperglycaemia significantly increased AGE-modified forms of total cellular and membrane annexin A2. The hyperglycemia-associated reduction in fibrinolytic activity was fully restored upon incubation with recombinant annexin A2 (rA2), but not AGE-modified annexin A2 or exogenous t-PA. Hyperglycaemia decreased t-PA, upregulated PAI-1 and induced AGE-related disruption of annexin A2 function, all of which contributed to the overall reduction in endothelial cell surface fibrinolytic activity. Further investigations to elucidate the underlying molecular mechanisms and pathophysiological implications of A2 derivatisation might ultimately lead to a better understanding of mechanisms of impaired vascular fibrinolysis, and to development of new interventional strategies for the thrombotic vascular complications in diabetes.

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Tumor-induced endothelial cell surface heterogeneity directly affects endothelial cell escape from a cell-mediated immune response in vitro

Human Vaccines & Immunotherapeutics ◽

10.4161/hv.22828 ◽

2013 ◽

Vol 9 (1) ◽

pp. 198-209 ◽

Cited By ~ 6

Author(s):

Petr Lokhov ◽

Elena E. Balashova

Keyword(s):

Immune Response ◽

Endothelial Cell ◽

Cell Surface ◽

Surface Heterogeneity ◽

Endothelial Cell Surface ◽

Cell Mediated Immune Response ◽

A Cell ◽

Immune Response In Vitro

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The Caenorhabditis elegans aristaless Orthologue, alr-1, Is Required for Maintaining the Functional and Structural Integrity of the Amphid Sensory Organs

Molecular Biology of the Cell ◽

10.1091/mbc.e05-03-0205 ◽

2005 ◽

Vol 16 (10) ◽

pp. 4695-4704 ◽

Cited By ~ 11

Author(s):

Morgan Tucker ◽

Matt Sieber ◽

Mary Morphew ◽

Min Han

Keyword(s):

Caenorhabditis Elegans ◽

Cell Shape ◽

Structural Integrity ◽

Genetic Interaction ◽

Critical Role ◽

Sensory Function ◽

Specific Cell ◽

Sensory Organs ◽

Human Disorders ◽

A Cell

The homeobox-containing aristaless-related protein ARX has been directly linked to the development of a number of human disorders involving mental retardation and epilepsy and clearly plays a critical role in development of the vertebrate central nervous system. In this work, we investigate the role of ALR-1, the Caenorhabditis elegans aristaless orthologue, in amphid sensory function. Our studies indicate that ALR-1 is required for maintenance of the amphid organ structure throughout larval development. Mutant analysis indicates a progressive loss in the amphid neurons' ability to fill with lipophilic dyes as well as a declining chemotactic response. The degeneration in amphid function corresponds with a failure of the glial-like amphid socket cell to maintain its specific cell shape and cell–cell contacts. Consistent with ALR-1 expression within the amphid socket cell, our results indicate a cell autonomous role for ALR-1 in maintaining cell shape. Furthermore, we demonstrate a role for ALR-1 in the proper morphogenesis of the anterior hypodermis. Genetic interaction tests also suggest that ALR-1 may function cooperatively with the cell adhesion processes in maintaining the amphid sensory organs.

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Cellular processing of bovine factors X and Xa by cultured bovine aortic endothelial cells.

Journal of Experimental Medicine ◽

10.1084/jem.162.2.559 ◽

1985 ◽

Vol 162 (2) ◽

pp. 559-572 ◽

Cited By ~ 13

Author(s):

P P Nawroth ◽

D McCarthy ◽

W Kisiel ◽

D Handley ◽

D M Stern

Keyword(s):

Endothelial Cell ◽

Cell Surface ◽

Factor Xa ◽

Factor X ◽

Aortic Endothelial Cells ◽

Endothelial Cell Surface ◽

Contrast Factor ◽

A Cell ◽

Cellular Processing ◽

Clotting Protein

Previous studies have shown that Factor X and Factor Xa bind specifically to distinct sites on the endothelial cell surface. Since the coagulant activity of a cell-bound clotting protein is dependent on its remaining on the cell surface, endocytosis and degradation studies have been carried out. Cell-bound Factor X was internalized at 0.07 fmol/min/10(6) cells, a rate slower than its dissociation from the cell surface. Endocytosed Factor X was not degraded, but was returned to the cell surface. In contrast, Factor Xa was internalized at an initial rate of 0.38 fmol/min/10(6) cells and subsequently degraded at about the same rate. The degradation of Factor Xa was prevented by chloroquine. These results suggest that Factor Xa is internalized and degraded by a lysosomal-dependent pathway. Studies with Factor X- and Xa-colloidal gold conjugates showed endocytosis proceeding at coated pit regions, and accumulation of Factor Xa-gold particles in lysosome-like structures. Endocytosis was studied as a clearance pathway for cell-bound Factor Xa by activating Factor X with Factors IXa and VIII on the endothelial cell surface. Endocytosis of the Factor Xa formed was significant, as only 44% of the Factor Xa formed was released into the supernatant, whereas the remainder was internalized and degraded. Thus, endocytosis of Factor Xa bound to its specific endothelial cell sites may be an important factor in the balance of vessel wall hemostatic mechanisms.

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