期刊
JOURNAL OF LIPID RESEARCH
卷 55, 期 9, 页码 1847-1854出版社
ELSEVIER
DOI: 10.1194/jlr.R045492
关键词
oxidized phospholipids; platelet-activating factor mimetics; infl ammation; platelet-activating factor receptor; cardiovascular disease
资金
- University Grants Commission, New Delhi, India [F: 41-1284/2012(SR)]
- Special Assistance Program (SAP) [F3-14/2012 (SAP II)]
- Vision Group in Science and Technology, Government of Karnataka, India [VGST/K-FIST (2010-11)/GRD-36/2013-14]
Mounting ambiguity persists around the functional role of the plasma form of platelet-activating factor acetylhydrolase (PAF-AH). Because PAF-AH hydrolyzes PAF and related oxidized phospholipids, it is widely accepted as an anti-inflammatory enzyme. On the other hand, its actions can also generate lysophosphatidylcholine (lysoPC), a component of bioactive atherogenic oxidized LDL, thus allowing the enzyme to have proinflammatory capabilities. Presence of a canonical lysoPC receptor has been seriously questioned for a multitude of reasons. Animal models of inflammation show that elevating PAF-AH levels is beneficial and not deleterious and overexpression of PAF receptor (PAF-R) also augments inflammatory responses. Further, many Asian populations have a catalytically inert PAF-AH that appears to be a severity factor in a range of inflammatory disorders. Correlation found with elevated levels of PAF-AH and CVDs has led to the design of a specific PAF-AH inhibitor, darapladib. However, in a recently concluded phase III STABILITY clinical trial, use of darapladib did not yield promising results. Presence of structurally related multiple ligands for PAF-R with varied potency, existence of multi-molecular forms of PAF-AH, broad substrate specificity of the enzyme and continuous PAF production by the so called bi-cycle of PAF makes PAF more enigmatic. jlr This review seeks to address the above concerns.
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