title: To hydrolyze or not to hydrolyze: the dilemma of platelet-activating factor acetylhydrolase.
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.
authors.affiliation: Department of Studies in Biochemistry, University of Mysore, Manasagangothri, Mysore 570006, India.
authors.forename: Gopal Kedihitlu
authors.initials: GK
authors.lastname: Marathe
authors.affiliation: Department of Studies in Biochemistry, University of Mysore, Manasagangothri, Mysore 570006, India.
authors.forename: Chaitanya
authors.initials: C
authors.lastname: Pandit
authors.affiliation: Department of Studies in Biochemistry, University of Mysore, Manasagangothri, Mysore 570006, India.
authors.forename: Chikkamenahalli Lakshminarayana
authors.initials: CL
authors.lastname: Lakshmikanth
authors.affiliation: Department of Studies in Biochemistry, University of Mysore, Manasagangothri, Mysore 570006, India.
authors.forename: Vyala Hanumanthareddy
authors.initials: VH
authors.lastname: Chaithra
authors.affiliation: Department of Studies in Biochemistry, University of Mysore, Manasagangothri, Mysore 570006, India.
authors.forename: Shancy Petsel
authors.initials: SP
authors.lastname: Jacob
authors.affiliation: Department of Studies in Biochemistry, University of Mysore, Manasagangothri, Mysore 570006, India.
authors.forename: Cletus Joseph Michael
authors.initials: CJ
authors.lastname: D'Souza
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000502:physiology*; D000818:Animals; D050197:Atherosclerosis / Q000201:enzymology / Q000276:immunology; D006801:Humans; D006868:Hydrolysis; D018836:Inflammation Mediators / Q000502:physiology; D010972:Platelet Activating Factor / Q000502:physiology; D012307:Risk Factors
chemical_list: D018836:Inflammation Mediators; D010972:Platelet Activating Factor; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase
keywords: cardiovascular disease; inflammation; oxidized phospholipids; platelet-activating factor mimetics; platelet-activating factor receptor