Ascorbic acid blocks the growth inhibitory effect of tumor necrosis factor-alpha on endothelial cells.
Impaired endothelial cell proliferation has been proposed to be an early, critical defect contributing to the development of atherosclerosis. Recent studies show that high plasma tumor necrosis factor (TNF)-alpha levels and low serum ascorbic acid (AA) levels correlate with atherosclerosis severity. Additionally, AA has been reported to have potential beneficial effects in preventing atherosclerosis. Based on these studies, we investigated the role of AA (< or =1mM) on TNF-alpha-mediated vascular endothelial cell growth inhibition in vitro. In accordance with previous reports, we found that TNF-alpha alone inhibited endothelial cell proliferation. Further studies revealed that AA alone enhanced endothelial cell proliferation and that AA blocked endothelial cell growth inhibition induced by TNF-alpha. By contrast, we observed no effect of AA on endothelial cell activation or nuclear entry of nuclear factor-kappaB in response to TNF-alpha. The protective effect of AA on endothelial cell proliferation was not simply the result of its antioxidant activity but did correlate with collagen IV expression by endothelial cells. AA pre-treatment of proliferating endothelial cells promoted retinoblastoma protein (Rb) phosphorylation and decreased p53 levels when compared to untreated cells. Furthermore, the addition of AA to TNF-alpha-treated proliferating endothelial cells blocked both the inhibition of retinoblastoma protein phosphorylation and enhanced p53 expression induced by TNF-alpha. Consistent with these results, we found that AA protects endothelial cells against TNF-alpha-induced apoptosis. These studies highlight the potential therapeutic role of AA in promoting endothelial cell proliferation during inflammatory conditions, such as atherosclerosis and cardiovascular disease.
Saeed
Rubina W
RW
Laboratory of Vascular Biology, Division of Medicinal Biochemistry, North Shore-Long Island Jewish Research Institute, Manhasset, New York 11030, USA.
Peng
Tina
T
Metz
Christine N
CN
D000328:Adult; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001205:Ascorbic Acid / Q000494:pharmacology*; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D018925:Chemokines / Q000096:biosynthesis; D024141:Collagen Type IV / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D040262:Receptors, Vascular Endothelial Growth Factor / Q000096:biosynthesis; D016160:Retinoblastoma Protein / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis
D000975:Antioxidants; D015815:Cell Adhesion Molecules; D018925:Chemokines; D024141:Collagen Type IV; D016328:NF-kappa B; D016160:Retinoblastoma Protein; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D040262:Receptors, Vascular Endothelial Growth Factor; D001205:Ascorbic Acid