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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:2041.)
© 2009 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Increased PAFAH and Oxidized Lipids Are Associated With Inflammation and Atherosclerosis in Hypercholesterolemic Pigs

Dieuwke De Keyzer; Sonia-Athina Karabina; Wenhzong Wei; Benjamine Geeraert; Dominique Stengel; Judit Marsillach; Jordi Camps; Paul Holvoet; Ewa Ninio

From the Atherosclerosis and Metabolism Unit, Department of Cardiovascular Diseases (D.DK., B.G., P.H.), Katholieke Universiteit Leuven, Belgium; INSERM UMRS937 (S.A.K., W.W., D.S., E.N.), Université Pierre et Marie Curie UPMC-Paris 6 and Faculté de Médecine Pierre et Marie Curie, Paris, France; and Centre de Recerca Biomèdica (J.M., J.C.), Hospital Universitari de Sant Joan, Catalunya, Spain. Current affiliation for W.W.: Department of Biochemistry, University of Nebraska, Lincoln.

Correspondence to Paul Holvoet, PhD, Atherosclerosis and Metabolism Unit, Department of Cardiovascular Diseases, Katholieke Universiteit Leuven; Herestraat 49, O&N1, PB 705, B-3000 Leuven, Belgium. E-mail paul.holvoet{at}med.kuleuven.be

Objective— To study the association of PAF-acetyl hydrolase (PAFAH) activity with inflammation, oxidative stress, and atherosclerosis in hypercholesterolemic swine.

Methods and Results— Cholesterol-rich diet feeding of miniature pigs was associated with an increase in PAFAH activity and an increase of the PAFAH to PON1 ratio. PLA2G7 RNA (coding for PAFAH) expression was increased in blood monocytes and plaque macrophages. Increased PAFAH activity was associated with higher plasma lysophosphatidylcholine and correlated with oxidized LDL. In THP1 monocytes and macrophages and in human blood-derived macrophages, oxidized LDL induced PLA2G7 RNA expression. Atherogenic diet feeding induced the accumulation of macrophages and oxidized LDL in the arterial wall leading to atherosclerosis. PAFAH activity correlated positively with plaque size and TNFalpha expression in plaque macrophages.

Conclusions— We demonstrated that an increase in PAFAH activity was associated with increased levels of lysophosphatidylcholine, oxidized LDL, and inflammation, resulting in accelerated atherosclerosis in hypercholesterolemic minipigs. The significant correlation between PLA2G7 RNA expression in plaque macrophages and plasma PAFAH activity suggests that the latter is a consequence, rather than a cause of macrophage accumulation. Our cell experiments suggest that oxidized LDL can induce PAFAH, resulting in accumulation of lysophosphatidylcholine that increases the inflammatory action of oxidized LDL.

In hypercholesterolemic minipigs, increased PAFAH activity was associated with increased circulating oxidized LDL. This association was further supported by our cell experiments, in which oxidized LDL induced PAFAH gene expression. The increase in PAFAH was also associated with an increase in proinflammatory gene expression in plaque macrophages and with accelerated atherosclerosis.

Key Words: atherosclerosis • oxidative stress • inflammation • PAFAH • genes