Peptides derived from serum amyloid A prevent, and reverse, aortic lipid lesions in apoE-/- mice.
Macrophages (Mphi) 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 A 2.1 (SAA2.1), that is synthesized by hepatocytes as part of a systemic response to acute injury. Our previous studies using cholesterol-laden J774 mouse Mphi showed that an N-terminal domain of SAA2.1 inhibits acyl-CoA:cholesterol acyltransferase activity, and a C-terminal domain enhances cholesteryl ester hydrolase activity. The net effect of this enzymatic regulation is to drive intracellular cholesterol to its unesterified state, the form readily exportable to an extracellular acceptor such as HDL. Here, we demonstrate that these domains from mouse SAA2.1, when delivered in liposomal formulation, are effective at preventing and reversing aortic lipid lesions in apolipoprotein E-deficient mice maintained on high-fat diets. Furthermore, mouse SAA peptides, in liposomal formulation, are effective at regulating cholesterol efflux in THP-1 human Mphi, 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 therefore may 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 antiatherogenic agents in humans.
Tam
Shui Pang
SP
Department of Pathology and Molecular Medicine, Queen's University, and The Syl and Molly Apps Research Centre, Kingston General Hospital, Kingston, Ontario, Canada.
Ancsin
John B
JB
Tan
Ruth
R
Kisilevsky
Robert
R
D000595:Amino Acid Sequence; D000818:Animals; D001011:Aorta / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency*; D050197:Atherosclerosis / Q000473:pathology / Q000517:prevention & control*; D002784:Cholesterol / Q000378:metabolism; D005260:Female; D006801:Humans; D008081:Liposomes / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D010446:Peptide Fragments / Q000494:pharmacology*; D000685:Serum Amyloid A Protein / Q000378:metabolism*; D002787:Sterol Esterase / Q000187:drug effects; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors
D001057:Apolipoproteins E; D008081:Liposomes; D010446:Peptide Fragments; D000685:Serum Amyloid A Protein; D002784:Cholesterol; D002785:Sterol O-Acyltransferase; D002787:Sterol Esterase