A new synthetic class A amphipathic peptide analogue protects mice from diet-induced atherosclerosis

Several synthetic class A peptide analogues have been shown to mimic many o f the properties of human apo A-I in vitro. A new peptide [acetyl-(AspTrpLe uLysAlaPheTyrAspLysValPheGluLysPheLysGluPhePhe)-NH2; 5F], with increased am phipathicity, was administered by intraperitoneal injection, 20 mug/day for 16 weeks, to C57BL/6J mice fed an atherogenic diet, Mouse apo A-I (MoA-I) (50 mug/day) or phosphate-buffered saline (PBS) injections were given to ot her mice as controls. Total plasma cholesterol levels and lipoprotein profi les were not significantly different between the treated and control groups , except that the mice receiving 5F or MoA-I had lower high density lipopro tein (HDL) cholesterol when calculated as a percentage of total cholesterol , No toxicity or production of antibodies to the injected materials was obs erved. When HDL was isolated from high fat diet-administered mice injected with 5F and presented to human artery wall cells in vitro together with hum an low density lipoprotein (LDL), there were substantially fewer lipid hydr operoxides formed and substantially less LDL-induced monocyte chemotactic a ctivity than with HDL from PBS-injected animals, Injection of human apo A-I produced effects similar to 5F on lipid peroxide formation and LDL-induced monocyte chemotactic activity, but injection of MoA-I was significantly le ss effective in reducing lipid hydroperoxide formation or lowering LDL-indu ced monocyte chemotactic activity, Mice receiving peptide 5F had significan tly less aortic atherosclerotic lesion area compared with mice receiving PB S, whereas lesion area in mice receiving MoA-I was similar to that of the P BS-injected animals. This is the first in vivo demonstration that a model c lass A amphipathic helical peptide has antiatherosclerotic properties. We c onclude that 5F inhibits lesion formation in high fat diet-administered mic e by a mechanism that does not involve changes in the lipoprotein profile, and may have potential in the prevention and treatment of atherosclerosis.