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J Lipid Res. 2014 Sep;55(9):1847-54. doi: 10.1194/jlr.R045492. Epub 2014 May 23.

To hydrolyze or not to hydrolyze: the dilemma of platelet-activating factor acetylhydrolase.

Author information

1
Department of Studies in Biochemistry, University of Mysore, Manasagangothri, Mysore 570006, India.

Abstract

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. This review seeks to address the above concerns.

KEYWORDS:

cardiovascular disease; inflammation; oxidized phospholipids; platelet-activating factor mimetics; platelet-activating factor receptor

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PMID:
24859738
PMCID:
PMC4617362
DOI:
10.1194/jlr.R045492
[Indexed for MEDLINE]
Free PMC Article

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