Abstract Fibrin plays an essential role in hemostasis as both the primary product of the coagulation cascade and the ultimate substrate for fibrinolysis. Fibrinolysis efficiency is greatly influenced ...by clot structure, fibrinogen isoforms and polymorphisms, the rate of thrombin generation, the reactivity of thrombus-associated cells such as platelets, and the overall biochemical environment. Regulation of the fibrinolytic system, like that of the coagulation cascade, is accomplished by a wide array of cofactors, receptors, and inhibitors. Fibrinolytic activity can be generated either on the surface of a fibrin-containing thrombus, or on cells that express profibrinolytic receptors. In a widening spectrum of clinical disorders, acquired and congenital defects in fibrinolysis contribute to disease morbidity, and new assays of global fibrinolysis now have potential predictive value in multiple clinical settings. Here, we summarize the basic elements of the fibrinolytic system, points of interaction with the coagulation pathway, and some recent clinical advances.
Annexin A2 (AnxA2) is a multifunctional calcium
(Ca
) and phospholipid-binding protein that is expressed in a wide spectrum of cells, including those participating in the inflammatory response. In ...acute inflammation, the interaction of AnxA2 with actin and adherens junction VE-cadherins underlies its role in regulating vascular integrity. In addition, its contribution to endosomal membrane repair impacts several aspects of inflammatory regulation, including lysosome repair, which regulates inflammasome activation, and autophagosome biogenesis, which is essential for macroautophagy. On the other hand, AnxA2 may be co-opted to promote adhesion, entry, and propagation of bacteria or viruses into host cells. In the later stages of acute inflammation, AnxA2 contributes to the initiation of angiogenesis, which promotes tissue repair, but, when dysregulated, may also accompany chronic inflammation. AnxA2 is overexpressed in malignancies, such as breast cancer and glioblastoma, and likely contributes to cancer progression in the context of an inflammatory microenvironment. We conclude that annexin AnxA2 normally fulfills a spectrum of anti-inflammatory functions in the setting of both acute and chronic inflammation but may contribute to disease states in settings of disordered homeostasis.
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.
The formation of new blood vessels from pre-existing vasculature, the process known as angiogenesis, is highly regulated by pro- and anti-angiogenic signaling molecules including growth factors and ...proteases. As an endothelial cell-surface co-receptor for plasminogen and tissue plasminogen activator, the annexin A2 (ANXA2) complex accelerates plasmin generation and facilitates fibrinolysis. Plasmin can subsequently activate a downstream proteolytic cascade involving multiple matrix metalloproteinases. Thus, in addition to maintaining blood vessel patency, the ANXA2 complex can also promote angiogenesis via its pro-fibrinolytic activity. The generation of ANXA2-deficient mice allowed us to first observe the pro-angiogenic role of ANXA2
. Further investigations have provided additional details regarding the mechanism for ANXA2 regulation of retinal and corneal angiogenesis. Other studies have reported that ANXA2 supports angiogenesis in specific tumor-related settings. Here, we summarize results from
studies that illustrate the pro-angiogenic role of ANXA2, and discuss the critical questions that may lead to an advanced understanding of the molecular mechanisms for ANXA2-mediated angiogenesis. Finally, highlights from studies on ANXA2-interacting agents offer potential therapeutic opportunities for the application of ANXA2-centered pharmaceuticals in angiogenesis-related disorders.
Molecular mechanisms of fibrinolysis Cesarman‐Maus, Gabriela; Hajjar, Katherine A.
British journal of haematology,
20/May , Letnik:
129, Številka:
3
Journal Article
Recenzirano
Summary
The molecular mechanisms that finely co‐ordinate fibrin formation and fibrinolysis are now well defined. The structure and function of all major fibrinolytic proteins, which include serine ...proteases, their inhibitors, activators and receptors, have been characterized. Measurements of real time, dynamic molecular interactions during fibrinolysis of whole blood clots can now be carried out in vitro. The development of gene‐targeted mice deficient in one or more fibrinolytic protein(s) has demonstrated expected and unexpected roles for these proteins in both intravascular and extravascular settings. In addition, genetic analysis of human deficiency syndromes has revealed specific mutations that result in human disorders that are reflective of either fibrinolytic deficiency or excess. Elucidation of the fine control of fibrinolysis under different physiological and pathological haemostatic states will undoubtedly lead to novel therapeutic interventions. Here, we review the fundamental features of intravascular plasmin generation, and consider the major clinical syndromes resulting from abnormalities in fibrinolysis.
Lipofuscin granules enclose mixtures of cross-linked proteins and lipids in proportions that depend on the tissue analyzed. Retinal lipofuscin is unique in that it contains mostly lipids with very ...little proteins. However, retinal lipofuscin also presents biological and physicochemical characteristics indistinguishable from conventional granules, including indigestibility, tendency to cause lysosome swelling that results in rupture or defective functions, and ability to trigger NLRP3 inflammation, a symptom of low-level disruption of lysosomes. In addition, like conventional lipofuscins, it appears as an autofluorescent pigment, considered toxic waste, and a biomarker of aging. Ocular lipofuscin accumulates in the retinal pigment epithelium (RPE), whereby it interferes with the support of the neuroretina. RPE cell death is the primary cause of blindness in the most prevalent incurable genetic and age-related human disorders, Stargardt disease and age-related macular degeneration (AMD), respectively. Although retinal lipofuscin is directly linked to the cell death of the RPE in Stargardt, the extent to which it contributes to AMD is a matter of debate. Nonetheless, the number of AMD clinical trials that target lipofuscin formation speaks for the potential relevance for AMD as well. Here, we show that retinal lipofuscin triggers an atypical necroptotic cascade, amenable to pharmacological intervention. This pathway is distinct from canonic necroptosis and is instead dependent on the destabilization of lysosomes. We also provide evidence that necroptosis is activated in aged human retinas with AMD. Overall, this cytotoxicity mechanism may offer therapeutic targets and markers for genetic and age-related diseases associated with lipofuscin buildups.
Proprotein convertase subtilisin/kexin-9 (PCSK9) enhances the degradation of hepatic low-density lipoprotein receptor (LDLR). Deletion of PCSK9, and loss-of-function mutants in humans result in lower ...levels of circulating LDL-cholesterol and a strong protection against coronary heart disease. Accordingly, the quest for PCSK9 inhibitors has major clinical implications. We have previously identified annexin A2 (AnxA2) as an endogenous binding partner and functional inhibitor of PCSK9. Herein, we studied the relevance of AnxA2 in PCSK9 inhibition and lipid metabolism in vivo. Plasma analyses of AnxA2(-/-) mice revealed: i) a ∼1.4-fold increase in LDL-cholesterol without significant changes in VLDLs or HDLs, and ii) a ∼2-fold increase in circulating PCSK9 levels. Western blotting and immunohistochemistry of AnxA2(-/-) tissues revealed that the LDLR was decreased by ∼50% in extrahepatic tissues, such as adrenals and colon. We also show that AnxA2-derived synthetic peptides block the PCSK9≡LDLR interaction in vitro, and adenoviral overexpression of AnxA2 in mouse liver increases LDLR protein levels in vivo. These results suggest that AnxA2 acts as an endogenous regulator of LDLR degradation, mostly in extrahepatic tissues. Finally, we identified an AnxA2 coding polymorphism, V98L, that correlates with lower circulating levels of PCSK9 thereby extending our results on the physiological role of AnxA2 in humans.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Annexin A2 (A2) is a multicompartmental, multifunctional protein that orchestrates a growing spectrum of biologic processes. At the endothelial cell surface, A2 and S100A10 (p11) form a ...heterotetramer, which accelerates tissue plasminogen activator-dependent activation of the fibrinolytic protease, plasmin. In antiphospholipid syndrome, anti-A2 antibodies are associated with clinical thrombosis, whereas overexpression of A2 in acute promyelocytic leukemia promotes hyperfibrinolytic bleeding. A2 is upregulated in hypoxia, and mice deficient in A2 are resistant to oxygen-induced retinal neovascularization, suggesting a role for A2 in human retinal vascular proliferation. In solid malignancies, the (A2•p11)(2) tetramer may promote cancer cell invasion, whereas in multiple myeloma A2 enables malignant plasmacyte growth and predicts prognosis. In the central nervous system, the p11 enables membrane insertion of serotonin receptors that govern mood. In the peripheral nervous system, p11 directs sodium channels to the plasma membrane, enabling pain perception. In cerebral cortex neurons, A2 stabilizes the microtubule-associated tau protein, which, when mutated, is associated with frontotemporal dementia. In inflammatory dendritic cells, A2 maintains late endosomal/lysosomal membrane integrity, thus modulating inflammasome activation and cytokine secretion in a model of aseptic arthritis. Together, these findings suggest an emerging, multifaceted role for A2 in human health and disease.
Annexin A2 is a multicompartmental protein that orchestrates a spectrum of dynamic membrane-related events. At cell surfaces, A2 forms the (A2•S100A10)2 complex which accelerates tissue plasminogen ...activator-dependent activation of the fibrinolytic protease, plasmin. Anti-A2 antibodies are associated with clinical thrombosis in antiphospholipid syndrome, whereas overexpression of A2 promotes hyperfibrinolytic bleeding in acute promyelocytic leukemia. A2 is upregulated in hypoxic tissues, and mice deficient in A2 are resistant to hypoxia-related retinal neovascularization in a model of diabetic retinopathy. Within the cell, A2 regulates membrane fusion processes involved in the secretion of pre-packaged, ultra-large molecules. In stimulated dendritic cells, A2 maintains lysosomal membrane integrity, thereby modulating inflammasome activation and cytokine secretion. Together, these findings suggest an emerging, multifaceted role for annexin A2 in human health and disease. The author's work has been inspired by numerous colleagues and mentors, and by the author's grandfather, and former ACCA member, Dr. J. Burns Amberson.
In a significant fraction of breast cancer patients, distant metastases emerge after years or even decades of latency. How disseminated tumour cells (DTCs) are kept dormant, and what wakes them up, ...are fundamental problems in tumour biology. To address these questions, we used metastasis assays in mice and showed that dormant DTCs reside on microvasculature of lung, bone marrow and brain. We then engineered organotypic microvascular niches to determine whether endothelial cells directly influence breast cancer cell (BCC) growth. These models demonstrated that endothelial-derived thrombospondin-1 induces sustained BCC quiescence. This suppressive cue was lost in sprouting neovasculature; time-lapse analysis showed that sprouting vessels not only permit, but accelerate BCC outgrowth. We confirmed this surprising result in dormancy models and in zebrafish, and identified active TGF-β1 and periostin as tumour-promoting factors derived from endothelial tip cells. Our work reveals that stable microvasculature constitutes a dormant niche, whereas sprouting neovasculature sparks micrometastatic outgrowth.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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