Role of vitamin C in prolyl hydroxylation under pathological conditions
Scurvy is the prototypical deficiency disease that links insufficient intake of vitamin C to impaired collagen synthesis [12]. Collagen synthesis is required for maintaining normal vascular function but also for tumor angiogenesis. Tumor growth relies on angiogenesis to provide the cancerous tissue with metabolic substrates, growth factors, and oxygen. Low vitamin C levels would therefore be expected to limit tumor growth by compromising collagen synthesis. Telang et al. [13] tested this hypothesis in mice incapable of ascorbic acid synthesis (Gulo−/− mice with a deletion of the L-gulono-γ-lactone oxidase gene) by measuring the effect of vitamin C supplementation on growth of implanted Lewis lung carcinoma cells. They found that Gulo−/− mice with low plasma vitamin C levels (< 5 μM) developed smaller tumors when the animals consumed a vitamin C-depleted diet compared to partially or fully vitamin C-supplemented animals. The tumors from the scorbutic animals showed multiple areas of hemorrhage, poorly formed blood vessels, and decreased collagen synthesis [13]. The authors suggest that patients with existing cancer may not benefit from vitamin C supplementation; however, vitamin C deficiency is not likely to be beneficial for human cancer patients.
Arterial Tortuosity Syndrome (ATS) is associated with abnormal collagen and elastin synthesis. Twisting and lengthening of major arteries, as well as hypermobility of the joints and laxity for the skin, are characteristics of this rare and heritable disease, which is caused by defects in the gene SLCA10 that codes for GLUT-10 [14]. Since GLUT-10 is localized in the rough endoplasmic reticulum (ER) [15] where proline and lysine hydroxylation take place and where collagen is prepared for secretion by the Golgi apparatus, Segade [15] hypothesized that the defective GLUT-10 in ATS leads to a decrease in uptake of dehydroascorbic acid by the ER, inadequate availability of ascorbic acid for prolyl and lysyl hydroxylases inside the ER, and to synthesis and extracellular deposition of abnormal collagen and elastin. Segade [15] further hypothesized that a major source of ascorbic acid in the ER is dehydroascorbic acid that is taken up by GLUT-10 in the ER membrane and reduced by protein disulfide isomerase in the lumen of the ER [16]. The dependence of ascorbate availability in the ER on GLUT-10 activity and its relevance to ATS remains to be demonstrated.
It is estimated that a third of preterm births are due to premature rupture of the fetal membranes [17]. Mercer et al. [18] tested the hypothesis that fetal membrane strength can be improved by vitamin C and E supplementation to increase collagen synthesis and to inhibit ROS-induced fetal membrane weakening. In a placebo-controlled study, 13 women with a singleton pregnancy received a combination of vitamin C (1000 mg/day) and vitamin E (400 IU/day) from the second trimester until delivery. Vitamin supplementation had no effect on rupture strength, did not affect the normal fetal membrane remodeling process that leads to weakening and rupture at term, and did not alter protein levels or activity of matrix metalloproteinase-9 (MMP-9), a marker of fetal membrane remodeling [19]. Collagen content of the fetal membranes was not measured in this study. Thus, supplementation did not have any obvious benefits.