Editorial Slides VP Watch, March 27, 2002, Volume 2, Issue 12

Ascorbic Acid, Wound Healing, and Vulnerable PlaqueVitamin C; Pro-Collagen vs. Antioxidant

Free radicals have been suggested for decades as the major factor involved in pathophysiology of chronic disorders like Alzheimer, rheumatoid arthritis, and atherosclerosis.

Oxidation of LDL by free radicals is known as the major factor for initiation of atherosclerosis. 1,2

Therefore antioxidant therapy (Vitamin C and E) has been studied for prevention or treatment of atherosclerosis.

However despite many epidemiological evidence the controversy about antioxidant therapy in atherosclerosis remains an issue.

Vitamin C is more than antioxidant:

Coenzyme for collagen production

Anti-oxidant • Antiinflammatory effects

Decreasing leukocyte adhesion to the endothelium

Inhibits OxLDL-induced leukocyte adhesion to endothelium

Inhibits activation of nuclear factor- kappa B• Improving endothelial dysfunction

Insufficient ascorbic acid, a required cofactor for prolylhydroxylase in collagen biosynthesis, causes the formation of unstable collagen. 2

Studies show greater wound integrity in animals that received higher dose of vitamin C compare to moderate dose of the vitamin. 7

In 1999 Nobuyo Maeda and his colleagues generated L-gulono-gamma-lactone oxidase deficient mice (Gulo-/-), a key enzyme for ascorbic acid synthesis, in their lab. The mutant mice, like humans, entirely depend on dietary vitamin C. 6

As highlighted in VP Watch of this week, Nakata and Maeda from University of North Carolina crossed Gulo-/- mice with ApoE-/- KO mice to study the effect of vitamin C deficiency on atherosclerosis.

They showed that low versus high vitamin C had no effect on the size of the atherosclerotic plaques that developed in the Gulo-/- Apoe-/- mice.

Aortic lesions at aortic sinus of the Gulo-/-Apoe-/- mice with high and low vitamin C

High Vit. C Low Vit. C Low Vit. CHigh Vit. C

Sections A, B, E, and F were stained for lipids with Sudan IVB and counterstained with hematoxylin. Their neighboring sections C, D, G, and H were stained for collagen with Sirius red. Sections A through D are from 4-month-old females fed Western-type diet. Sections E

through H are from 9-month-old males fed normal chow. Arrows in E indicate small vessels in adventitia. Bar=100 µm.

From: Yukiko Nakata and Nobuyo Maeda; Circulation 2002 105: 1485 - 1490; published online before print March 4 2002, doi:10.1161/01.CIR.0000012142.69612.25

Collagen-Stained Area in Advance Atherosclerotic Plaques

0

20

40

60

80

High Vit. CLow Vit. C

P=0.002

P=0.002P=0.0003

Green bars represent mean±SEM in high vitamin C plaques, and blue bars represent mean±SEM in low vitamin C plaques.

Adapted from: Vulnerable Atherosclerotic Plaque Morphology in Apolipoprotein E–Deficient Mice Unable to Make Ascorbic Acid ; Yukiko Nakata and Nobuyo Maeda ; Circulation 2002 105: 1485 - 1490

Conclusion:

I. Vitamin C does not alter either foam cell formation or the size of atherosclerotic plaques.

II. Vitamin C deficiency compromises deposition of collagen in the atherosclerotic plaques and significantly influences their collagen content and collagen in the adventitia surrounding vessels with plaques.

Questions:

I. This study only shows the effect of lack of vitamin C on atherosclerosis and plaque vulnerability. The question is whether excess vitamin C can reverse atherosclerosis or stabilize plaque.

II. Vitamin C has been long known for its wound healing properties, knowing vulnerable plaques as sites of injury/wound in arterial wall, would vitamin C administration help increase plaque stability?

III. If so, should the treatment be administered systemic or locally?

Questions:

IV. Vitamin C has two major roles, collagen production and antioxidation, which one is more dominant as far as atherosclerosis and vulnerable plaque?

Suggestion:

VP.org Editorial Suggestion:

- Please email your thoughts to:

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

1. Witztum JL, Steinberg D. Role of oxidized low density lipoprotein in atherogenesis. J Clin Invest. 1991; 88: 1785–1792.[Medline]

2. Heinecke JW. Oxidants and antioxidants in the pathogenesis of atherosclerosis: implications for the oxidized low density lipoprotein hypothesis. Atherosclerosis. 1998; 141: 1–15.[Medline]

3. Buettner GR. The pecking order of free radicals and antioxidants: lipid peroxidation, -tocopherol, and ascorbate. Arch Biochem Biophys. 1993; 300: 535–543.[Medline]

4. Martin A, Frei B. Both intracellular and extracellular vitamin C inhibit atherogenic modification of LDL by human vascular endothelial cells. Arterioscler Thromb Vasc Biol. 1997; 17: 1583–1590.[Abstract/Full Text]

5. Bowie AG, O’Neill LA. Vitamin C inhibits NF- B activation by TNF via the activation of p38 mitogen-activated protein kinase. J Immunol.;. 2000; 165: 7180–7188.[Abstract/Full Text]

6. Maeda N, Hagihara H, Nakata Y, et al. Aortic wall damage in mice unable to synthesize ascorbic acid. Proc Natl Acad Sci U S A. 2000; 97: 841–846.[Abstract/Full Text]

7. Silverstein RJ, Landsman AS.; The effects of a moderate and high dose of vitamin C on wound healing in a controlled guinea pig model. J Foot Ankle Surg. 1999 Sep-Oct;38(5):333

8. Naghavi M, Madjid M, Khan MR, Mohammadi RM, Willerson JT, Casscells SW.; New developments in the detection of vulnerable plaque. ; Curr Atheroscler Rep. 2001 Mar;3(2):125-35. Review.

9. Free Radic Res 2001 Dec;35(6):967-78; Supplementation with vitamin E but not with vitamin C lowers lipid peroxidation in vivo in mildly hypercholesterolemic men.Kaikkonen J, Porkkala-Sarataho E, Morrow JD, Roberts LJ 2nd, Nyyssonen K, Salonen R, Tuomainen TP, Ristonmaa U, Poulsen HE, Salonen JT.

10. Gale CR, Ashurst HE, Powers HJ, Martyn CN.; Antioxidant vitamin status and carotid atherosclerosis in the elderly.Am J Clin Nutr 2001 Sep;74(3):402-8

11. Vulnerable Atherosclerotic Plaque Morphology in Apolipoprotein E–Deficient Mice Unable to Make Ascorbic Acid Yukiko Nakata and Nobuyo Maeda ; Circulation 2002 105: 1485 – 1490

12. Rocnik EF, Chan BM, Pickering JG. Evidence for a role of collagen synthesis in arterial smooth muscle cell migration. J Clin Invest. 1998; 101: 1889–1898.[Abstract/Full Text]

References