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Abstract
Angiostatin is derived from enzymatic degradation of plasminogen and it has endogenous anti-angiogenic properties. Although tumor cells, macrophages, platelets, and neutrophils generate high amount of angiostatin, its expression is increased in inflammatory conditions. Moreover, angiostatin binds to integrin αvβ3, ATP synthase, and angiomotin, which expressed on neutrophils. Activated neutrophils are essential to innate immune response, but also cause tissue damage through production of reactive oxygen species (ROS) and increase lifespan. In this article, it suggests several mechanism of angiostatin as immune regulator for neutrophils in inflammatory conditions; complex with integrin αvβ3 and F1F0 ATP synthase on lipid raft, attenuate polarization, and ROS production. These data provide possible exploit of double-edged role of neutrophils in acute inflammatory pathologies to preserve beneficial effect and minimize tissue damage.
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Figure 1.
Schematic diagram for mechanism of action of angiostatin (ANG) in acute inflammation (30). ANG inhibits neutrophil adhesion as well as trans-endothelial migration in an acute inflammation setting by inhibiting the leading edge actin dynamics. Angiostatin is endocytosed in activated neutrophils via lipid raft domains, which express integrin αvβ3 as well as F1F0 ATP synthase. It can be hypothesized that ANG binds to a GTPase activating protein (GAP) associated angiomotin (AMOT) that inhibits guanosine triphophate (GTP) recycling required for F-actin aggregation at the leading edge, thereby inhibiting neutrophil chemotaxis. Decrease of the mitochondrial ATP synthesis via inhibition of F1F0 ATP synthase leads to mitochondrial redox inhibition and reduction in ROS production and ultimately induces apoptosis, as evidenced through the presence of apoptotic nuclear bodies (depicted in blue) after 4 hours of angiostatin incubation with LPS (30).
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