Editorial Slides VP Watch, January 23, 2002, Volume 2, Issue 3

Oral Apo A-I Mimetic Peptide for Reduction of Atherosclerosis

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

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

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.

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

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

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

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

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.

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

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.

Questions:I.

Questions:

Suggestion:VP.org Editorial Suggestion:

- Please email your thoughts to:

Discussion-Group@VP.org or DG@VP.org

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 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.

References

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