Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0162871 (abdominal aortic aneurysm)
 8,664 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Leukotrienes (LTs) derived from 5-lipoxygenase (5-LO) activity are most widely known for their actions during acute inflammation and asthma. 5-LO/LT pathway involvement in cardiovascular disease (CVD) pathogenesis has come to the forefront based on provocative human genetic/population and animal studies leading to the hypothesis that this pathway promotes atherosclerosis, abdominal aortic aneurysm, and myocardial infarction/reperfusion injury via increased leucocyte chemotaxis, vascular inflammation and enhanced permeability, and subsequent tissue/matrix degeneration. A series of pre-clinical studies have tested this hypothesis by means of genetic or pharmacological inhibition of either the LT biosynthesis axis (5-LO, 5-LO-activating protein, LTA(4) hydrolase, LTC(4) synthase) or the cognate LT receptors. Here, we summarize, compare, and analyse these animal studies and relate their findings to human disease pathogenesis. We draw a complex picture of 5-LO/LT participation in cardiovascular disorders, which is further complicated by marked differences between species. Moreover, we discuss how the cytokine footprint of the respective pathological conditions determines the expression level and hence, the contribution of components of the pathway to the overall disease state. Current knowledge implies a role for 5-LO and LTs during the early/acute phase of CVD, but our understanding of a putative 5-LO/LT involvement in more advanced stages of CVD is limited, thereby preventing simple extrapolation of findings from animal studies to humans.
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PMID:The 5-lipoxygenase/leukotriene pathway in preclinical models of cardiovascular disease. 2009 52

Leukotrienes (LTs) are arachidonic acid-derived lipid mediators involved in the pathogenesis and progression of diverse inflammatory disorders. The cysteinyl-leukotrienes LTC(4), LTD(4), and LTE(4) are important mediators of asthma, and LTB(4) has recently been implicated in atherosclerosis. Here we report that mRNA levels for the three key enzymes/proteins in the biosynthesis of cysteinyl-leukotrienes, 5-lipoxygenase (5-LO), 5-LO-activating protein (FLAP), and LTC(4) synthase (LTC(4)S), are significantly increased in the wall of human abdominal aortic aneurysms (AAAs). In contrast, mRNA levels of LTA(4) hydrolase, the enzyme responsible for the biosynthesis of LTB(4), are not increased. Immunohistochemical staining of AAA wall revealed focal expression of 5-LO, FLAP, and LTC(4)S proteins in the media and adventitia, localized in areas rich in inflammatory cells, including macrophages, neutrophils, and mast cells. Human AAA wall tissue converts arachidonic acid and the unstable epoxide LTA(4) into significant amounts of cysteinyl-leukotrienes and to a lesser extent LTB(4). Furthermore, challenge of AAA wall tissue with exogenous LTD(4) increases the release of matrix metalloproteinase (MMP) 2 and 9, and selective inhibition of the CysLT1 receptor by montelukast blocks this effect. The increased expression of LTC(4)S, together with the predominant formation of cysteinyl-leukotrienes and effects on MMPs production, suggests a mechanism by which LTs may promote matrix degradation in the AAA wall and identify the components of the cysteinyl-leukotriene pathway as potential targets for prevention and treatment of AAA.
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PMID:Increased expression of leukotriene C4 synthase and predominant formation of cysteinyl-leukotrienes in human abdominal aortic aneurysm. 2107 89