Low vitamin C and increased oxidative stress and cell death in mice that lack the sodium-dependent vitamin C transporter SVCT2

Abstract

The Sodium-dependent Vitamin C Transporter (SVCT2) is responsible for the transport of vitamin C into cells in multiple organs, either from the blood or cerebrospinal fluid. Mice null for SVCT2 (SVCT2(−/−)) do not survive past birth but cause of death has not yet been ascertained. Following mating of SVCT2(+/−) males and SVCT2(+/−) females, fewer SVCT2(−/−) and (+/−) were observed than would be expected according to Mendelian ratios. Vitamin C levels in SVCT2(−/ −), (+/−) and (+/+) were genotype-dependent. SVCT2(−/−) fetuses had significantly lower vitamin C levels than littermates in placenta, cortex, and lung but not in liver (the site of vitamin C synthesis). Low vitamin C levels in placenta and cortex were associated with elevations in several different markers of oxidative stress; malondialdehyde, isoketals, F 2 -isoprostanes, and F 4 -neuroprostanes. Oxidative stress was not elevated in fetal SVCT2(−/−) lung tissue despite low vitamin C levels. In addition to the expected severe hemorrhage in cortex, we also found hemorrhage in the brain stem, which was accompanied by cell loss. We found evidence of increased apoptosis in SVCT2(−/−) mice and disruption of the basement membrane in fetal brain. Together these data show that vitamin C is critical for maintaining vitamin C levels in fetal and placental tissues and that lack of SVCT2, and resulting low vitamin C levels, results in fetal death, and in SVCT(−/−) that survive the gestation period, in oxidative stress and cell death.

Sodium-Dependent Vitamin C Transporter 2 Deficiency Causes Hypomyelination and Extracellular Matrix Defects in the Peripheral Nervous System

“…In wild-type sciatic nerves we found ascorbic acid concentrations of 2.3-3.1 mol/g. These values are in the range of previously reported values for adult mouse brain (2.0 -4.2 mol/g) and just below those for fetal mouse brain (2.9 -4.0 mol/g) and fetal rat brain (3.6 -4.0 mol/g) (Kratzing et al, 1985;Kuo et al, 2004;Harrison et al, 2010aHarrison et al, , 2010c. Since peripheral nerves contain as much ascorbic acid as brain tissue, it appears that the peripheral nerve is equally ascorbic acid-privileged as the brain, which supports the assumption that ascorbic acid may have important functions in the peripheral nervous system.…”

“…As shown in Figure 1 D, ascorbic acid concentrations were significantly reduced at P20, P60, and P300 in SVCT2 ϩ/Ϫ sciatic nerves compared to controls. Ascorbic acid concentrations in wild-type peripheral nerves were slightly lower than those reported for brain tissue (Harrison et al, 2010c), which are known to be very high compared to other organs and blood (Harrison and May, 2009). …”

Vitamin C Deficiency in the Brain Impairs Cognition, Increases Amyloid Accumulation and Deposition, and Oxidative Stress in APP/PSEN1 and Normally Aging Mice

“…The SVCT2 is expressed 31 in muscle fibers, and thus transporter deficiency could conceivably lead to weakness. We did not specifically measure the decrease in vitamin C in muscle although the heterozygous mutation, although data from brain and other organs in these mice 32 , suggests the mutation would result in a similar vitamin C decrease of 30–50%. Muscular weakness in aging is likely a combination of muscular atrophy and neuronal changes, particularly at the neuromuscular junction 33 .…”

Caveolin-1–mediated internalization of the vitamin C transporter SVCT2 in microglia triggers an inflammatory phenotype

“…This transcription factor is activated not only by receptorspecific ligands but also directly by oxidizing agents (71). In the absence of SVCT2, there is a decrease in ascorbate uptake, which enhances ROS production (72). Increased ROS production might be sufficient to stimulate nuclear translocation of NF-kB because it enhances the proteasome dependent degradation of the inhibitor of NF-kB (IkB) (43).…”