Submitted on May 11, 2005
Revised on July 15, 2005
Accepted on July 19, 2005
Peptides derived from serum amyloid A prevent, and reverse, aortic lipid lesions in apoE -/- mice
Shui Pang Tam, John B. Ancsin, Ruth Tan, and Robert Kisilevsky
Pathology DCept., Queen's University, Kingston General Hospital, Kingston, Ontario K7L 3N6
Corresponding Author: kisilevsky{at}cliff.path.queensu.ca
Macrophages at sites of acute tissue injury accumulate and export cholesterol quickly. This metabolic activity is likely dependent on the physiological function of a major acute phase protein, serum amyloid A2.1 (SAA2.1) that is synthesized by hepatocytes as part of a systemic response to acute injury. Our previous studies using cholesterol-laden J774 mouse macrophages showed that an N-terminal domain of SAA2.1 inhibits acylCoA:cholesterol acyl transferase activity, and a C-terminal domain enhances cholesterol ester hydrolase activity. The net effect of this enzymatic regulation is to drive intracellular cholesterol to its un-esterified state, the form readily exportable to an extracellular acceptor such as HDL. Herein, we demonstrate that these domains from mouse SAA2.1, when delivered in liposomal formulation, are effective in preventing and reversing aortic lipid lesions in apoE -/- mice maintained on high fat diets. Furthermore, mouse SAA peptides, in liposomal formulation, are effective in regulating cholesterol efflux in THP-1 human macrophages, and homologous domains from human SAA are effective in mouse J774 cells. These peptides operate at the level of the foam cell in the reverse cholesterol pathway and may therefore be used in conjunction with other agents that act more distally in this process. Such human peptides, or small molecule mimics of their structure, may prove to be potent anti-atherogenic agents in humans.
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