Anti-inflammatory HDL becomes pro-inflammatory during the acute phase response. Loss of protective effect of HDL against LDL oxidation in aortic wall cell cocultures

• Published in: The Journal of clinical investigation Vol. 96; no. 6; pp. 2758 - 2767
• Main Authors: Van Lenten, B J, Hama, S Y, de Beer, F C, Stafforini, D M, McIntyre, T M, Prescott, S M, La Du, B N, Fogelman, A M, Navab, M
• Format: Journal Article
• Language: English
• Published: United States 01-12-1995
• Subjects: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Animals; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Aorta - cytology; Aorta - physiology; Aryldialkylphosphatase; Base Sequence; Cell Adhesion; Cells, Cultured; Ceruloplasmin - biosynthesis; Chemokine CCL2 - biosynthesis; Coculture Techniques; Croton Oil; DNA Primers; Endothelium, Vascular - cytology; Endothelium, Vascular - drug effects; Endothelium, Vascular - physiology; Esterases - metabolism; Gene Expression; Humans; Inflammation - physiopathology; Lipoproteins, HDL - isolation & purification; Lipoproteins, HDL - metabolism; Lipoproteins, HDL - pharmacology; Male; Molecular Sequence Data; Monocytes - cytology; Monocytes - physiology; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - physiology; Oxidation-Reduction; Phospholipases A - metabolism; Rabbits
• ISSN: 0021-9738
• DOI: 10.1172/jci118345

We previously reported that high density lipoprotein (HDL) protects against the oxidative modification of low density lipoprotein (LDL) induced by artery wall cells causing these cells to produce pro-inflammatory molecules. We also reported that enzyme systems associated with HDL were responsible for this anti-inflammatory property of HDL. We now report studies comparing HDL before and during an acute phase response (APR) in both humans and a croton oil rabbit model. In rabbits, from the onset of APR the protective effect of HDL progressively decreased and was completely lost by day three. As serum amyloid A (SAA) levels in acute phase HDL (AP-HDL) increased, apo A-I levels decreased 73%. Concomitantly, paraoxonase (PON) and platelet activating factor acetylhydrolase (PAF-AH) levels in HDL declined 71 and 90%, respectively, from days one to three. After day three, there was some recovery of the protective effect of HDL. AP-HDL from human patients and rabbits but not normal or control HDL (C-HDL) exhibited increases in ceruloplasmin (CP). This increase in CP was not seen in acute phase VLDL or LDL. C-HDL incubated with purified CP and re-isolated (CP-HDL), lost its ability to inhibit LDL oxidation. Northern blot analyses demonstrated enhanced expression of MCP-1 in coculture cells treated with AP-HDL and CP-HDL compared to C-HDL. Enrichment of human AP-HDL with purified PON or PAF-AH rendered AP-HDL protective against LDL modification. We conclude that under basal conditions HDL serves an anti-inflammatory role but during APR displacement and/or exchange of proteins associated with HDL results in a pro-inflammatory molecule.