Abstract
Two homologous apoA-I mimetic peptides, 3F-2 and 3F(14), differ in their in vitro antiatherogenic properties (Epand, R. M., Epand, R. F., Sayer, B. G., Datta, G., Chaddha, M., and Anantharamaiah, G. M. (2004) J. Biol. Chem. 279, 51404-51414). In the present work, we demonstrate that the peptide 3F-2, which has more potent anti-inflammatory activity in vitro when administered intraperitoneally to female apoE null mice (20 microg/mouse/day) for 6 weeks, inhibits atherosclerosis (lesion area 15,800 +/- 1000 microm(2), n = 29), whereas 3F(14) does not (lesion area 20,400 +/- 1000 microm(2), n = 26) compared with control saline administered (19,900 +/- 1400 microm(2), n = 22). Plasma distribution of the peptides differs in that 3F-2 preferentially associates with high density lipoprotein, whereas 3F(14) preferentially associates with apoB-containing particles. After intraperitoneal injection of (14)C-labeled peptides, 3F(14) reaches a higher maximal concentration and has a longer half-time of elimination than 3F-2. A study of the effect of these peptides on the motional and organizational properties of phospholipid bilayers, using several NMR methods, demonstrates that the two peptides insert to different extents into membranes. 3F-2 with aromatic residues at the center of the nonpolar face partitions closer to the phospholipid head group compared with 3F(14). In contrast, only 3F(14) affects the terminal methyl group of the acyl chain, decreasing the (2)H order parameter and at the same time also decreasing the molecular motion of this methyl group. This dual effect of 3F(14) can be explained in terms of the cross-sectional shape of the amphipathic helix. These results support the proposal that the molecular basis for the difference in the biological activities of the two peptides lies with their different interactions with membranes.
Highlights
When the apoA-I mimetic peptide D-4F is administered to mice that possess inflammatory HDL, the HDL is converted to a form that has inhibitory activity against LDL-induced monocyte chemotaxis [11]
We have shown that in class A amphipathic helical peptides possessing the same polar face with identical charged residue distribution, subtle differences in the arrangement of the hydrophobic residues result in only subtle differences in physical properties and interaction with lipids but result in large differences in biological properties [12, 13]
The present study demonstrates that one of the 3F peptides, 3F-2, which was able to inhibit LDL-induced monocyte chemotaxis [12], protects against atherosclerotic lesion formation when administered to apoE null mice that spontaneously develop atherosclerosis, whereas the analogous peptide 3F14 (Fig. 1) that did not inhibit LDLinduced monocyte chemotaxis does not inhibit lesion formation
Summary
Materials—Cholesterol and 1-palmitoyl-2-oleoyl phosphatidylcholine (POPC) were obtained from Avanti Polar Lipids (Alabaster, AL). The spectra were obtained in 16 scans in 65,536 data points over a 5.297-kHz spectral width (6.187 s acquisition time). The spectra were acquired using the J-modulated spin sort pulse sequence over a 42.373-kHz spectral width in 65,536 data points (0.773 s acquisition time). The samples were spun at a rate of 5500 Hz. The spectra were recorded at a carbon resonance frequency of 125.77 MHz with a sweep width of 43 kHz, and the acquisition time was set to 0.5 s. Raw spectra were recorded using 16,384 data points (acquisition time less than 0.3 s), and the data were processed without zero filling and with exponential multiplication (lb ϭ 50 Hz). The CSAs were determined from the 31P NMR spectra recorded at at least three different spinning speeds, and the average result is reported
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
