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Enzymes. 2015;38:145-55. doi: 10.1016/bs.enz.2015.09.002. Epub 2015 Oct 17.

Plasma PAFAH/PLA2G7 Genetic Variability, Cardiovascular Disease, and Clinical Trials.

Author information

1
Sorbonne Universités, UPMC, INSERM UMRS 933, Hôpital Armand-Trousseau, Paris, France.
2
Sorbonne Universités, UPMC, INSERM UMRS 1166, ICAN, Genomics and Pathophysiology of Cardiovascular Diseases Team, Paris, France. Electronic address: ewa.ninio@upmc.fr.

Abstract

PAFAH is specific for short acyl groups esterified at the sn-2 position of glycerol in phospholipids, and apart from PAF, it hydrolyzes oxidized phospholipids produced during LDL oxidation. As the majority of the plasma PAFAH activity is bound in humans to LDL, it is also called the lipoprotein-associated phospholipase A2 (Lp-PLA2), and it was associated with the proinflammatory processes in atherosclerosis. The epidemiological studies in Caucasian populations demonstrated that high PAFAH levels might be a risk factor for cardiovascular disease through generation of proinflammatory lysoPC/lysoPAF and oxidized fatty free acids and led to the development of darapladib, a reversible PAFAH inhibitor. In the preclinical study in diabetic and hypercholesterolemic pigs, darapladib decreased both plasma and in situ lesion PAFAH/Lp-PLA2 activity, reduced lesion lysoPC content, and also reduced the complex coronary lesion development by reducing the necrotic core. In the recently published double-blind trial with darapladib (STABILITY study), it was shown that darapladib did not affect the time to cardiovascular death, myocardial infarction, or stroke. Similarly, in the SOLID-TIMI 52 study, darapladib did not reduce the risk of major coronary events; for those reasons, the clinical trials with darapladib will probably definitely stop in this pathology. Finally, in the absence of a tangible effect of V279F loss-of-function mutation on the cardiovascular risk in Asiatic populations and no effect of A379V polymorphism which modifies PAFAH activity in Caucasians, combined with no effect of the anti-PAFAH/Lp-PLA2 drug darapladib in clinical trials, let us conclude that it is unlikely that PAFAH could be implicated in atherosclerosis per se. We rather believe that PAFAH/Lp-PLA2 is a biomarker of atherosclerosis.

KEYWORDS:

Atherosclerosis; Darapladib; Lp-PLA2; PAFAH; PLA2G7

PMID:
26612651
DOI:
10.1016/bs.enz.2015.09.002

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