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  • Title: Homocysteine increases the expression of vascular endothelial growth factor by a mechanism involving endoplasmic reticulum stress and transcription factor ATF4.
    Author: Roybal CN, Yang S, Sun CW, Hurtado D, Vander Jagt DL, Townes TM, Abcouwer SF.
    Journal: J Biol Chem; 2004 Apr 09; 279(15):14844-52. PubMed ID: 14747470.
    Abstract:
    Vascular endothelial growth factor (VEGF) plays a key role in the development and progression of diabetic retinopathy. We previously demonstrated that amino acid deprivation and other inducers of endoplasmic reticulum-stress (ER stress) up-regulate the expression of VEGF in the retinal-pigmented epithelial cell line ARPE-19. Because homocysteine causes ER stress, we hypothesized that VEGF expression is increased by ambient homocysteine. dl-Homocysteine-induced VEGF expression was investigated in confluent ARPE-19 cultures. Northern analysis showed that homocysteine increased steady state VEGF mRNA levels 4.4-fold. Other thiol-containing compounds, including l-homocysteine thiolactone and DTT, induced VEGF expression 7.9- and 8.8-fold. Transcriptional run-on assays and mRNA decay studies demonstrated that the increase in VEGF mRNA levels was caused by increased transcription rather than mRNA stabilization. VEGF mRNA induction paralleled that of the ER-stress gene GRP78. Homocysteine treatment caused transient phosphorylation of eIF2alpha and an increase in ATF4 protein level. Overexpression of a dominant-negative ATF4 abolished the VEGF response to homocysteine treatment and to amino acid deprivation. VEGF mRNA expression by ATF4-/- MEF did not respond to homocysteine treatment and the response was restored with expression of wild-type ATF4. These studies indicate that expression of the pro-angiogenic factor VEGF is increased by homocysteine and other thiol-containing reductive compounds via ATF4-dependent activation of VEGF transcription.
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