TDAG51 is induced by homocysteine, promotes detachment-mediated programmed cell death, and contributes to the cevelopment of atherosclerosis in hyperhomocysteinemia.
Hyperhomocysteinemia is an independent risk factor for cardiovascular disease and accelerates atherosclerosis in apoE-/- mice. Despite the observations that homocysteine causes endoplasmic reticulum (ER) stress and programmed cell death (PCD) in cultured human vascular endothelial cells, the cellular factors responsible for this effect and their relevance to atherogenesis have not been completely elucidated. We report here that homocysteine induces the expression of T-cell death-associated gene 51 (TDAG51), a member of the pleckstrin homology-related domain family, in cultured human vascular endothelial cells. This effect was observed for other ER stress-inducing agents, including dithiothreitol and tunicamycin. TDAG51 expression was attenuated in homozygous A/A mutant eukaryotic translation initiation factor 2 alpha mouse embryonic fibroblasts treated with homocysteine or tunicamycin, suggesting that ER stress-induced phosphorylation of eukaryotic translation initiation factor 2 alpha is required for TDAG51 transcriptional activation. Transient overexpression of TDAG51 elicited significant changes in cell morphology, decreased cell adhesion, and promoted detachment-mediated PCD. In support of these in vitro findings, TDAG51 expression was increased and correlated with PCD in the atherosclerotic lesions from apoE-/- mice fed hyperhomocysteinemic diets, compared with mice fed a control diet. Collectively, these findings provide evidence that TDAG51 is induced by homocysteine, promotes detachment-mediated PCD, and contributes to the development of atherosclerosis observed in hyperhomocysteinemia.
Department of Pathology and Molecular Medicine, McMaster University and the Henderson Research Centre, Hamilton, Ontario L8V 1C3, Canada.
Gazi S
GS
Hossain
Johannes V
JV
van Thienen
Geoff H
GH
Werstuck
Ji
J
Zhou
Sudesh K
SK
Sood
Jeffrey G
JG
Dickhout
A B Lawrence
AB
de Koning
Damu
D
Tang
Dongcheng
D
Wu
Erling
E
Falk
Ranjana
R
Poddar
Donald W
DW
Jacobsen
Kezhong
K
Zhang
Randal J
RJ
Kaufman
Richard C
RC
Austin
D000818:Animals; D017209:Apoptosis; D001161:Arteriosclerosis / Q000473:pathology*; D015152:Blotting, Northern; D002448:Cell Adhesion; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D003001:Cloning, Molecular; D003433:Crosses, Genetic; D018076:DNA, Complementary / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology; D019084:Fluorescent Antibody Technique, Indirect; D020869:Gene Expression Profiling; D015723:Gene Library; D006710:Homocysteine / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D020138:Hyperhomocysteinemia / Q000150:complications / Q000473:pathology*; D020287:In Situ Nick-End Labeling; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000378:metabolism; D013347:Subcellular Fractions; D013997:Time Factors; D014018:Tissue Distribution; D014157:Transcription Factors / Q000737:chemistry* / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection; D014415:Tunicamycin / Q000494:pharmacology; D014471:Umbilical Veins
D018076:DNA, Complementary; C491923:PHLDA1 protein, human; C114072:Phlda1 protein, mouse; D012333:RNA, Messenger; D014157:Transcription Factors; D006710:Homocysteine; D014415:Tunicamycin