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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2002;22:1213.)
© 2002 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Human Secretory Phospholipase A₂ Mediates Decreased Plasma Levels of HDL Cholesterol and ApoA-I in Response to Inflammation in Human ApoA-I Transgenic Mice

Uwe J.F. Tietge; Cyrille Maugeais; Sissel Lund-Katz; David Grass; Frederick C. deBeer; Daniel J. Rader

From the Department of Medicine (U.J.F.T., C.M., D.J.R.), University of Pennsylvania School of Medicine, and Children’s Hospital of Philadelphia (S.L.-K.), Philadelphia, Pa; Xenogen Corp (D.G.), Cranbury, NJ; and the University of Kentucky (F.C.dB.), Lexington.

Correspondence to Daniel J. Rader, MD, University of Pennsylvania Medical Center, 654 BRB II/III, 421 Curie Blvd, Philadelphia, PA 19104-6160. E-mail rader{at}mail.med.upenn.edu

Objective— Plasma levels of high density lipoprotein (HDL) cholesterol and apolipoprotein (apo)A-I are decreased in inflammatory states. Secretory phospholipase A₂ (sPLA₂), an acute-phase protein, may play a key role in the pathophysiology of this phenomenon.

Methods and Results— To investigate the effects of sPLA₂ on human-like HDL particles in vivo, we generated transgenic mice overexpressing human apoA-I and human sPLA₂ (apoA-I/sPLA₂ mice). Compared with apoA-I mice, apoA-I/sPLA₂ mice had significantly lower plasma levels of phospholipids, HDL cholesterol, and apoA-I (each P<0.01). HDL from apoA-I/sPLA₂ mice was significantly depleted in phospholipids and cholesteryl esters (each P<0.001) but was enriched in protein and triglycerides (each P<0.001). As assessed by gel filtration and nondenaturing gel electrophoresis, sPLA₂ overexpression in apoA-I mice resulted in a dramatic shift of the HDL particle size toward smaller particles. Furthermore, virtually all plasma sPLA₂ in apoA-I/sPLA₂ mice was found in association with the HDL fraction. The acute-phase response was induced in apoA-I/sPLA₂ double-transgenic and apoA-I single-transgenic mice by intraperitoneal lipopolysaccharide (LPS) injection. Plasma sPLA₂ was significantly increased after LPS injection in apoA-I/sPLA₂ mice. Twelve hours after LPS administration, plasma total cholesterol, HDL cholesterol, apoA-I, and phospholipids were unchanged in apoA-I transgenic control mice but had decreased significantly in the apoA-I/sPLA₂ mice (-57%, -62%, and -54%, -61%, respectively; each P<0.001). Both groups of mice had increased plasma levels of serum amyloid A (SAA) in response to LPS. To test the hypothesis that SAA may be an in vivo activator of sPLA₂, we specifically overexpressed SAA in apoA-I/sPLA₂ mice by means of liver-directed gene transfer. Despite high plasma levels of SAA, plasma lipid and lipoprotein profiles were not different than those in control mice.

Conclusions— These results in a mouse model of human-like HDL indicate that sPLA₂ expression significantly influences HDL particle size and composition and demonstrate that an induction of sPLA₂ is required for the decrease in plasma HDL cholesterol in response to inflammatory stimuli in mice and that this effect is independent of SAA.

Key Words: apolipoproteins • lipoproteins • inflammation • phospholipase • HDL

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