TDAG51 Is Induced by Homocysteine, Promotes Detachment-mediated Programmed Cell Death, and Contributes to the Development of Atherosclerosis in Hyperhomocysteinemia

Gazi S Hossain,Johannes V Van Thienen,Geoff H Werstuck,Ji Zhou,Sudesh K Sood,Jeffrey G Dickhout,A.B.Lawrence De Koning,Damu Tang,Dongcheng Wu,Erling Falk,Ranjana Poddar,Donald W Jacobsen,Kezhong Zhang,Randal J Kaufman,Richard C Austin

doi:10.1074/jbc.m212897200

Abstract

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.

Highlights

Hyperhomocysteinemia is an independent risk factor for cardiovascular disease and accelerates atherosclerosis in apoE؊/؊ mice
T-cell death-associated gene 51 (TDAG51) Is a Homocysteine-inducible Gene—To identify candidate proapoptotic genes induced by homocysteine, RNA from control or homocysteine-treated human umbilical vein endothelial cells (HUVEC) was subjected to mRNA differential display, as described previously [13]
Recent studies have demonstrated that hyperhomocysteinemia accelerates the development of atherosclerosis [5, 6] and that homocysteine causes endoplasmic reticulum (ER) stress, leading to growth arrest and programmed cell death (PCD) in cultured vascular endothelial cells [10, 18, 19]

Summary

Introduction

Hyperhomocysteinemia is an independent risk factor for cardiovascular disease and accelerates atherosclerosis in apoE؊/؊ mice. In support of these in vitro findings, TDAG51 expression and PCD were increased and co-localized in the atherosclerotic lesions from apoEϪ/Ϫ mice having diet-induced hyperhomocysteinemia, compared with control mice. These studies provide novel evidence that TDAG51 is induced by homocysteine, promotes detachment-mediated PCD, and contributes to atherosclerotic lesion development observed in hyperhomocysteinemia.

Results

Conclusion