Low vitamin C and increased oxidative stress and cell death in mice that lack the sodium-dependent vitamin C transporter SVCT2.
The sodium-dependent vitamin C transporter (SVCT2) is responsible for the transport of vitamin C into cells in multiple organs, from either the blood or the cerebrospinal fluid. Mice null for SVCT2 (SVCT2(-/-)) do not survive past birth but the cause of death has not yet been ascertained. After mating of SVCT2(+/-) males and SVCT2(+/-) females, fewer SVCT2(-/-) and SVCT2(+/-) progeny were observed than would be expected according to Mendelian ratios. Vitamin C levels in SVCT2(-/-), SVCT2(+/-), and SVCT2(+/+) 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 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 SVCT2 is critical for maintaining vitamin C levels in fetal and placental tissues and that the lack of SVCT2, and the resulting low vitamin C levels, results in fetal death and, in SVCT2(-/-) mice that survive the gestation period, in oxidative stress and cell death.
Harrison
F E
FE
Department of Medicine, Vanderbilt University, Nashville, TN 37232, USA. Fiona.Harrison@Vanderbilt.edu
Dawes
S M
SM
Meredith
M E
ME
Babaev
V R
VR
Li
L
L
May
J M
JM
D000818:Animals; D001205:Ascorbic Acid / Q000097:blood*; D001921:Brain / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D016923:Cell Death / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D005838:Genotype; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D029363:Organic Anion Transporters, Sodium-Dependent / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D018384:Oxidative Stress / Q000235:genetics*; D010920:Placenta / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D060347:Sodium-Coupled Vitamin C Transporters; D027981:Symporters / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D014018:Tissue Distribution; D015854:Up-Regulation / Q000235:genetics
D029363:Organic Anion Transporters, Sodium-Dependent; C555165:Slc23a2 protein, mouse; D060347:Sodium-Coupled Vitamin C Transporters; D027981:Symporters; D008315:Malondialdehyde; D001205:Ascorbic Acid