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Thromboxane synthase inhibitors inhibit the final enzyme (thromboxane synthase) in the synthesis of thromboxane. Ifetroban is a potent and selective thromboxane receptor antagonist. [10] Dipyridamole antagonizes this receptor too, but has various other mechanisms of antiplatelet activity as well.
The human thromboxane A (TXA) synthase is a 60 kDa cytochrome P450 protein with 533 amino acids and a heme prosthetic group. This enzyme, anchored to the endoplasmic reticulum, is found in platelets, monocytes, and several other cell types. The NH2 terminus contains two hydrophobic segments whose secondary structure is believed to be helical.
Activation of TP receptors stimulates vascular endothelial cell pro-inflammatory responses such as increased expression of cell surface adhesion proteins (i.e. ICAM-1, VCAM-1, and E-selectin); stimulates apoptosis (i.e. cell death) of CD4+ and CD8+ lymphocytes; causes the chemokinesis (i.e. cell movement) of native T cells; and impairs the ...
Thromboxane A 2 (TXA 2) is generated from prostaglandin H 2 by thromboxane-A synthase in a metabolic reaction which generates approximately equal amounts of 12-hydroxyheptadecatrienoic acid (12-HHT). Aspirin irreversibly inhibits platelet cyclooxygenase 1 preventing the formation of prostaglandin H 2, and therefore TXA 2.
COX-1 is responsible for the synthesis of prostaglandin and thromboxane in many types of cells, including the gastro-intestinal tract and blood platelets. COX-2 plays a major role in prostaglandin biosynthesis in inflammatory cells and in the central nervous system.
Notable ones include thromboxane synthase (CYP5), prostacyclin synthase (CYP8), and CYP74A (allene oxide synthase). The most common reaction catalyzed by cytochromes P450 is a monooxygenase reaction, e.g., insertion of one atom of oxygen into the aliphatic position of an organic substrate (RH), while the other oxygen atom is reduced to water:
The released ATP acts on purinergic receptors on endothelial cells, triggering the synthesis and release of several vasodilators, like nitric oxide (NO) and prostacyclin (PGI 2). [40] [41] The current model of leukocyte adhesion cascade includes many steps mentioned in Table 1. [42]
The underlying mechanism for the deleterious effect proposes that endothelial cells lining the microvasculature in the body express COX-2, whose selective inhibition results in levels of prostaglandin I2 (PGI2, prostacyclin) down-regulated relative to thromboxane (since COX-1 in platelets is unaffected).