Selective macrophage ascorbate deficiency suppresses early atherosclerosis.
To test whether severe ascorbic acid deficiency in macrophages affects progression of early atherosclerosis, we used fetal liver cell transplantation to generate atherosclerosis-prone apolipoprotein E-deficient (apoE(-/-)) mice that selectively lacked the ascorbate transporter (SVCT2) in hematopoietic cells, including macrophages. After 13 weeks of chow diet, apoE(-/-) mice lacking the SVCT2 in macrophages had surprisingly less aortic atherosclerosis, decreased lesion macrophage numbers, and increased macrophage apoptosis compared to control-transplanted mice. Serum lipid levels were similar in both groups. Peritoneal macrophages lacking the SVCT2 had undetectable ascorbate; increased susceptibility to H(2)O(2)-induced mitochondrial dysfunction and apoptosis; decreased expression of genes for COX-2, IL1β, and IL6; and decreased lipopolysaccharide-stimulated NF-κB and antiapoptotic gene expression. These changes were associated with decreased expression of both the receptor for advanced glycation end products and HIF-1α, either or both of which could have been the proximal cause of decreased macrophage activation and apoptosis in ascorbate-deficient macrophages.
Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Vladimir R
VR
Babaev
Richard R
RR
Whitesell
Liying
L
Li
MacRae F
MF
Linton
Sergio
S
Fazio
James M
JM
May
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D001205:Ascorbic Acid / Q000009:adverse effects / Q000378:metabolism; D001206:Ascorbic Acid Deficiency / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000209:etiology / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control*; D002478:Cells, Cultured; D018450:Disease Progression; D005260:Female; D020022:Genetic Predisposition to Disease / Q000517:prevention & control; D017737:Macrophages, Peritoneal / Q000378:metabolism* / Q000473:pathology / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009928:Organ Specificity / Q000235:genetics; D029363:Organic Anion Transporters, Sodium-Dependent / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D060347:Sodium-Coupled Vitamin C Transporters; D027981:Symporters / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D013997:Time Factors
D001057:Apolipoproteins E; D029363:Organic Anion Transporters, Sodium-Dependent; C555165:Slc23a2 protein, mouse; D060347:Sodium-Coupled Vitamin C Transporters; D027981:Symporters; D001205:Ascorbic Acid