Human apolipoprotein AI mimetic peptides for the treatment of atherosclerosis.
The effects of apolipoprotein (Apo) AI mimetic peptide synthesized from D- and L-amino acids on atherosclerotic lesion formation were investigated in low-density lipoprotein (LDL) receptor-deficient mice on a Western diet and in apoE null mice. In addition, their effects on the inflammatory changes induced in LDL-receptor mice fed a Western diet following influenza A infection were studied. When apolipoprotein AI mimetic peptides synthesized from either D- or L-amino acids were administered to LDL-receptor null mice, only peptides synthesized from D-amino acids were stable in the circulation and enhanced the ability of high-density lipoprotein (HDL) to protect LDL against oxidation. Administration of the peptide D-4F to LDL-receptor null mice and apoE null mice decreased lesion size. Additionally, in LDL receptor null mice after influenza infection, D-4F treatment increased plasma HDL levels and paraoxonase activity, and inhibited increased in LDL-cholesterol and peak levels of interleukin-6 post-infection. Injection of female mice with male macrophages, and subsequent measurement of the male 'sry' gene, revealed a marked increase in macrophage traffic into the aortic arch after infection that was prevented by administration of D-4F. This indicates that: (i) oral D-4F has powerful anti-atherosclerotic properties, and (ii) the loss of the anti-inflammatory properties of HDL after influenza infection in mice is associated with increased arterial macrophage traffic that can be prevented by administration of D-4F.
Department of Medicine, David Geffen School of Medicine, 10833 Le Conte Avenue, University of California, Los Angeles, Los Angeles, CA 90095-1679, USA. mnavab@mednet.ucla.edu
Mohamad
M
Navab
G M
GM
Anantharamaiah
Srinivasa T
ST
Reddy
Brian J
BJ
Van Lenten
Greg
G
Hough
Alan
A
Wagner
Kenta
K
Nakamura
David W
DW
Garber
Geeta
G
Datta
Jere P
JP
Segrest
Susan
S
Hama
Alan M
AM
Fogelman
D000818:Animals; D016632:Apolipoprotein A-I / Q000627:therapeutic use*; D001161:Arteriosclerosis / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D004195:Disease Models, Animal; D006801:Humans; D007251:Influenza, Human / Q000150:complications / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects
D016632:Apolipoprotein A-I; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; C465468:D-4F peptide; D011973:Receptors, LDL