Vitamin C has roles as both an antioxidant and in collagen production. A study found that vitamin C deficiency in mice compromised collagen deposition in atherosclerotic plaques, reducing collagen content. However, vitamin C levels did not affect plaque size or foam cell formation. While vitamin C may stabilize plaques by increasing collagen, more research is needed to determine if excess vitamin C can reverse atherosclerosis or if local vitamin C treatment could increase plaque stability. The study demonstrates vitamin C's role in collagen production for plaque stability but did not determine its dominant role in atherosclerosis.

1. Editorial Slides
VP Watch, March 27, 2002, Volume 2, Issue 12
Ascorbic Acid, Wound Healing, and Vulnerable Plaque
Vitamin C; Pro-Collagen vs. Antioxidant

2.  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.

3.  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

4.  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

5.  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.

6. 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

7. Collagen-Stained Area in Advance Atherosclerotic Plaques
0
20
40
60
80
High Vit. C
Low Vit. C
P=0.002
P=0.002
P=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

8. 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.

9. 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?

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

11. Suggestion:
VP.org Editorial Suggestion:
- Please email your thoughts to:
Discussion-Group@VP.org or DG@VP.org

12. 1. Witztum JL, Steinberg D. Role of oxidized low density lipoprotein in atherogenesis. J Clin Invest. 1991; 88: 1785–1792.[Medline]
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hypothesis. Atherosclerosis. 1998; 141: 1–15.[Medline]
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Biophys. 1993; 300: 535–543.[Medline]
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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]
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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.
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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
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Clin Invest. 1998; 101: 1889–1898.[Abstract/Full Text]
References