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213 oral apo ai mimetic peptide for reduction of atherosclerosis
1. Editorial Slides
VP Watch, January 23, 2002, Volume 2, Issue 3
Oral Apo A-I Mimetic Peptide for Reduction of
Atherosclerosis
2. Though there is variety of treatment methods for
atherosclerosis, there is clearly a need for an oral
agent inducing reduction of atherosclerosis.
Badimon, Fuster, and colleagues in 1989 showed
that administration of homologous HDL-VHDL
lipoprotein fraction to cholesterol-fed rabbits,
dramatically inhibited the extent of aortic fatty
streaks and lowered lipid deposition in the arterial
wall and liver without modification of the plasma
lipid levels.1
3. Shah et al. A single large dose of recombinant
apoA-I Milano rapidly increases the cholesterol
efflux–promoting capacity, mobilizes tissue
cholesterol, and reduces plaque lipid and
macrophage contents within 48 hours in apoE-
deficient mice. 6
Apo A-I Milano significantly reduced intimal
thickening and macrophage content after
balloon injury in cholesterol-fed rabbits without
a change in arterial total cholesterol content. 6
4. There are 2 mechanisms for apo A-I
( major apolipoprotein of HDL) which
protects against atherosclerosis in animals:
5,6
a. Reverse cholesterol transport,
b. Removal of low levels of oxidized lipids,
"seeding molecules" required to oxidize
LDL.
5. Infusion or transgenic expression of apo A-
I, the major apolipoprotein of HDL, protects
against atherosclerosis in animals. 2,3
Apo A-I and class A amphipathic helical
peptide analogs of apo A-I remove low
levels of oxidized lipids and prevent LDL
oxidation. 4,5
6. Eriksson et al. showed that after injection of
liposomes containing pro-apolipoprotein A-I,
fecal excretion of cholesterol increases. 7
Shah et al. demonstrated successful transfer
of apo A-I Milano gene into vascular smooth
muscle cells and bone marrow cells using
recombinant adeno-associated virus. 8
7. As highlighted in this week VP Watch, Navab
and colleagues found that only apolipoprotein A-I
mimetic peptide synthesized from D-amino acids
is stable in the circulation and enhanced the ability
of HDL to protect LDL against oxidation when
given orally to LDL receptor-null mice. 10
They discussed that mammalian enzymes such as
proteases recognize peptides and proteins
synthesized from L-amino acids but rarely
recognize those synthesized from D-amino
acids.10
8. They showed that when a peptide synthesized
from D-amino acids (D-4F) is administered orally
to LDL receptor-null mice on a Western diet,
lesions decrease by 79%. When added to the
drinking water of apoE-null mice, D-4F decreases
lesions by approximately 75%. 10
The plasma total cholesterol was not significantly
different for mice not receiving peptide and those
which received peptide. 10
9. At 4-weeks old, D-4F was added to the drinking water to give concentrations of
0.05 mg/mL (n=8 mice), 0.1 mg/mL (n=8 mice), 0.2 mg/mL (n=8 mice), 0.4
mg/mL (n=8 mice), 1.0 mg/mL (n=4 mice), or 2.0 mg/mL (n=4 mice), and no D-4F
was added to the drinking water of control mice (None) (n=13 mice). The mice
consumed approximately 2.5 mL of water per day. Values are mean±SEM.
*P<0.05 compared with control mice.
Reduction in plaque lesion area
Mohamad Navab, G.M. Anantharamaiah, Susan Hama, David W. Garber, Manjula Chaddha, Greg Hough,
Roger Lallone, and Alan M. Fogelman; Oral Administration of an Apo A-I Mimetic Peptide Synthesized From
D-Amino Acids Dramatically Reduces Atherosclerosis in Mice Independent of Plasma Cholesterol;
Circulation 2002 105: 290 - 292.
10. Navab and his colleagues recently reported
data on 27 patients with coronary
atherosclerosis who did not smoke, were not
diabetic, did not take hypolipidemic
medications, and whose total plasma
cholesterol, triglycerides, LDL, and HDL were
indistinguishable from 31 age- and sex-
matched normal controls. They showed that
27 coronary artery disease patients had
dysfunctional HDL similar to the LDL
receptor-null and apoE-null mice without D-
4F. 11
11. Conclusion:
I. Orally administered apo A-I mimetic peptides
synthesized from D-amino acids dramatically inhibit
atherosclerosis independent of changes in total
plasma or HDL-cholesterol.
II. This apo A-I mimetic peptides could be useful for the
prevention and treatment of atherosclerosis and other
chronic inflammatory illnesses that are caused by
oxidized lipids.
15. 1. Badimon JJ, Badimon L, Galvez A, Dische R, Fuster V.; High density lipoprotein
plasma fractions inhibit aortic fatty streaks in cholesterol-fed rabbits. Lab Invest.
1989 Mar;60(3):455-61.
2. Badimon JJ, Badimon L, Fuster V. Regression of atherosclerotic lesions by high
density lipoprotein plasma fraction in the cholesterol-fed rabbit. J Clin Invest.
1990; 85: 1234–1241.
3. Plump AS, Scott CJ, Breslow JL. Human apolipoprotein A-I gene expression
increases high density lipoprotein and suppresses atherosclerosis in the
apolipoprotein E-deficient mouse. Proc Natl Acad Sci U S A. 1994; 91: 9607–
9611.
4. Navab M, Hama SY, Cooke CJ, et al. Normal high density lipoprotein inhibits
three steps in the formation of mildly oxidized low density lipoprotein: step 1. J
Lipid Res. 2000; 41: 1481–1494.
5. Navab M, Hama SY, Anantharamaiah GM, et al. Normal high density lipoprotein
inhibits three steps in the formation of mildly oxidized low density lipoprotein:
steps 2 and 3. J Lipid Res. 2000; 41: 1495–1508.
6. Shah PK, Yano J, Reyes O, et al. High-dose recombinant apolipoprotein A-
Imilano mobilizes tissue cholesterol and rapidly reduces plaque lipid and
macrophage content in apolipoprotein E-deficient mice: potential implications for
acute plaque stabilization. Circulation. 2001; 103: 3047–3050.
7. Mohamad Navab, G.M. Anantharamaiah, Susan Hama, David W. Garber,
Manjula Chaddha, Greg Hough, Roger Lallone, and Alan M. Fogelman; Oral
References
16. 8. Eriksson M, Carlson LA, Miettinen TA, Angelin B.; Stimulation of fecal steroid
excretion after infusion of recombinant proapolipoprotein A-I. Potential reverse
cholesterol transport in humans. Circulation 1999 Aug 10;100(6):594-8
9. Shah PK, Kaul S, Nilsson J, Cercek B.; Exploiting the vascular protective effects
of high-density lipoprotein and its apolipoproteins: an idea whose time for testing
is coming, part II.Circulation. 2001 Nov 13;104(20):2498-502. Review.
10. Mohamad Navab, G.M. Anantharamaiah, Susan Hama, David W. Garber,
Manjula Chaddha, Greg Hough, Roger Lallone, and Alan M. Fogelman; Oral
Administration of an Apo A-I Mimetic Peptide Synthesized From D-Amino Acids
Dramatically Reduces Atherosclerosis in Mice Independent of Plasma
Cholesterol; Circulation 2002 105: 290 - 292.
11. Navab M, Hama SY, Hough GP, et al. A cell-free assay for detecting HDL that is
dysfunctional in preventing the formation of or inactivating oxidized
phospholipids. J Lipid Res. 2001; 42: 1308–1317.
References