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 Ascorbic Acid-Independent Synthesis of Collagen in Mice. 
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Ascorbate Wizard
Ascorbate Wizard

Joined: Tue Nov 22, 2005 3:16 pm
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Location: Lisle, IL
Post Ascorbic Acid-Independent Synthesis of Collagen in Mice.
Historically, when the Foundation reviewed a study that used mice, we dismissed the study's value because mice make their own vitamin C. Guinea pigs make better models because these pigs, like humans, suffer the GULO mutation and can't make vitamin C. And guinea pigs, unlike mice, have apo(a) (Lp(a) and suffer the same atherosclerosis when their diet is deficient in vitamin C.

New strains of mice have been genetically engineered with the GULO defect. This means that these mice can not make their own vitamin C, and thus they are more interesting, and experiments with them are more representative of the human condition.

The following study explored the effect of low/no vitamin C on cancer tumor formation. These researchers report that tumors still form (probably to their surprise) in the absence of vitamin C. But note that the mice don't survive without the vitamin.

Ascorbic Acid-Independent Synthesis of Collagen in Mice.
http://www.ncbi.nlm.nih.gov/entrez/quer ... query_hl=2

abstract wrote:
The mouse has become the most important model organism for the study of human physiology and disease. However, until the recent generation of mice lacking the enzyme gulanolactone oxidase (Gulo), the final enzyme in the ascorbic acid biosynthesis pathway, examining the role of ascorbic acid in various biochemical processes using this model organism has not been possible.

In the mouse, similar to most mammals but unlike humans who carry a mutant copy of this gene, Gulo produces ascorbic acid from glucose.

We report here that while ascorbic acid is essential for survival, its absence does not lead to measurable changes in proline hydroxylation. Vitamin C deficiency had no significant effect on the hydroxylation of proline and collagen production during tumor growth or in angiogenesis associated with tumor or mammary gland growth. This suggests that factors other than ascorbic acid can support proline hydroxylation and collagen synthesis in vivo. Furthermore, the failure of Gulo -/- mice to thrive on a vitamin C-deficient diet therefore suggests that ascorbic acid plays a critical role in survival other than the maintenance of the vasculature.



Earlier studies of GULO mice showed that their cholesterol becomes elevated, and that they suffered vascular (aortic) damage. The next study found that "The most striking pathological finding in our current study is the presence of abnormalities in the aortic walls of the vitamin C-deficient mice."


Aortic wall damage in mice unable to synthesize ascorbic acid
http://www.pubmedcentral.nih.gov/articl ... d=10639167

abstract wrote:
By inactivating the gene for l-gulono-γ-lactone oxidase, a key enzyme in ascorbic acid synthesis, we have generated mice that, like humans, depend on dietary vitamin C. Regular chow, containing about 110 mg/kg of vitamin C, is unable to support the growth of the mutant mice, which require l-ascorbic acid supplemented in their drinking water (330 mg/liter). Upon withdrawal of supplementation, plasma and tissue ascorbic acid levels decreased to 10–15% of normal within 2 weeks, and after 5 weeks the mutants became anemic, began to lose weight, and die. Plasma total antioxidative capacities were approximately 37% normal in homozygotes after feeding the unsupplemented diet for 3–5 weeks. As plasma ascorbic acid decreased, small, but significant, increases in total cholesterol and decreases in high density lipoprotein cholesterol were observed. The most striking effects of the marginal dietary vitamin C were alterations in the wall of aorta, evidenced by the disruption of elastic laminae, smooth muscle cell proliferation, and focal endothelial desquamation of the luminal surface. Thus, marginal vitamin C deficiency affects the vascular integrity of mice unable to synthesize ascorbic acid, with potentially profound effects on the pathogenesis of vascular diseases. Breeding the vitamin C-dependent mice with mice carrying defined genetic mutations will provide numerous opportunities for systematic studies of the role of antioxidants in health and disease.


The Pauling/Rath unified theory predicts that similar aortic damage in humans, with the Lp(a) cholesterol molecule in our blood, would form atherosclerotic lesions. These lesions form as the sticky Lp(a) is attracted to the lysine binding sites. This is a healing process as these binding sites appear after a blood vessel wall cracks or is otherwise injured, usually by the force of the heartbeat.


Finally, researchers should not expect GULO mice to produce Lp(a)/apo(a), because of their "normal" endogenous vitamin C production, and no time to adapt (naturally select) for this mutation among offspring.

The following report is from a project that added a gene to mice that caused them to produce the apo(a) molecule. (Note: LDL + apo(a) = Lp(a))

See: LBL Scientists Create New Strains of Mice for Heart Disease Research (1993)
http://www.lbl.gov/Science-Articles/Arc ... udies.html

Rubin wrote:
In the first project, the introduction of a human gene that codes for a protein called apolipoprotein(a), or apo(a), made mice far more susceptible to the development of fatty lesions that lead to hardening of the arteries.

Says Rubin, "Apo(a) transgenic mice developed lesions at a rate of about 20 times greater than non-transgenic litter mates when both were fed an atherogenic diet. The mechanism by which mice with high levels of apo(a) became atherosclerotic appeared to mimic the development of atherosclerosis in humans."


If any reader is aware of a strain of mice with BOTH the GULU defect and the apo(a) addition, please let us know.

_________________
Owen R. Fonorow, Orthomolecular Naturopath


Fri Dec 16, 2005 8:26 am
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