Tufts University, School of Medicine, Boston, MA, United StatesTaishan Medical University, Taian, ChinaUniversity of California, Irvine, CA, United Statesa Department of Veterans Affairs Healthcare System, Atherosclerosis Research Center, 5901 East Seventh Street, Long Beach, CA 90822, United States
刊名
Journal of Cardiovascular Pharmacology and Therapeutics
Objective: Synthetic class A amphipathic helical peptide analogs of apolipoprotein-AI are emerging therapeutic approaches under investigation for atherosclerosis. Utilizing retroinverso sequencing, we designed reverse-D4F peptide with 18 D-amino acids containing 4 phenylalanine residues and reverse order that allows the side chain residues to be of exact alignment and superimposable to those of the parent L-amino acid peptide. This study examined the effect of Rev-D4F on atherosclerosis in apo...更多
Objective: Synthetic class A amphipathic helical peptide analogs of apolipoprotein-AI are emerging therapeutic approaches under investigation for atherosclerosis. Utilizing retroinverso sequencing, we designed reverse-D4F peptide with 18 D-amino acids containing 4 phenylalanine residues and reverse order that allows the side chain residues to be of exact alignment and superimposable to those of the parent L-amino acid peptide. This study examined the effect of Rev-D4F on atherosclerosis in apolipoprotein E -null mice and the underlying mechanisms. Materials/Methods: ApoE-null mice were fed a chow diet and administered water , Rev-D4F, or L4F mimetic peptides orally in drinking water for 6 weeks. Aortic root atherosclerotic lesion area, lesion macrophage content, and the ability of plasma high-density lipoprotein to influence monocyte chemotaxis were measured. Results: Rev-D4F significantly decreased aortic sinus atherosclerotic lesion area and lesion macrophage content without affecting plasma total and HDL-cholesterol levels in apoE-null mice. The HDL from Rev-D4F-treated mice showed enhanced anti-inflammatory monocyte chemotactic activity, while low-density lipoprotein exhibited reduced proinflammatory activity. In in vitro studies, Rev-D4F inhibited LDL oxidation, endothelial cell vascular cell adhesion molecule 1 , and monocyte chemotactic factor 1 expression, and monocyte adhesion to aortic endothelial cells. Conclusions: The Rev-D4F inhibits atherosclerosis by inhibiting endothelial inflammatory/ oxidative events and improving HDL function. The data suggest that Rev-D4F may be an effective apoAI mimetic peptide for further development in preventing atherosclerosis.收起
