Homocysteine thiolactone induces apoptotic DNA damage mediated by increased intracellular hydrogen peroxide and caspase 3 activation in HL-60 cells

Huang, Rachel; Huang, Sheu-Mai; Lin, Bou-Shu; Wei, Jeng-Shu; Liu, Tsan‐Zon

doi:10.1016/s0024-3205(01)01066-9

Cited by 122 publications

(67 citation statements)

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“…Recent studies have now shown that homocysteine induces programmed cell death (PCD) in cultured human vascular endothelial cells and that this effect involves activation of the UPR (17,18). Furthermore, the activation of caspase-3 was shown to be essential for this process, a result consistent with the ability of homocysteine thiolactone, a cyclic thioester of homocysteine synthesized by specific aminoacyl-tRNA synthetases (12), to induce PCD in HL-60 cells (19). Although these studies provide in vitro evidence that homocysteine and its derivatives can promote PCD, further studies are required to identify the proapoptotic factors involved in this process as well as their in vivo relevance to the development of atherosclerosis.…”

mentioning

confidence: 76%

“…Recent studies have demonstrated that hyperhomocysteinemia accelerates the development of atherosclerosis (5,6) and that homocysteine causes ER stress, leading to growth arrest and PCD in cultured vascular endothelial cells (10,18,19). Despite these findings, the proapoptotic factors implicated in this process and the in vivo relevance to atherogenesis have yet to be identified.…”

Section: Discussionmentioning

confidence: 99%

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

Hossain

Thienen

Werstuck

et al. 2003

Journal of Biological Chemistry

210

194

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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␣ mouse embryonic fibroblasts treated with homocysteine or tunicamycin, suggesting that ER stress-induced phosphorylation of eukaryotic translation initiation factor 2␣ is required for TDAG51 transcriptional activation. Transient overexpression of TDAG51 elicited significant changes in cell morphology, decreased cell adhesion, and promoted detachmentmediated 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.

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mentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

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

Hossain

Thienen

Werstuck

et al. 2003

Journal of Biological Chemistry

210

194

View full text Add to dashboard Cite

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“…Furthermore, caspase-3 activation is essential for homocysteine-induced apoptotic cell death, a result consistent with the ability of homocysteine thiolactone, a cyclic thioester derivative of homocysteine, 87 to induce apoptotic cell death in HL-60 cells. 88 Although caspase-7 and/or caspase-12 activation have been implicated in the coupling of ER stress to apoptotic cell death, [89][90][91] there are presently no reported studies examining the effect of homocysteine on the activation of these caspases. Given that apoptosis has been widely documented to occur in animal and human atherosclerotic lesions, and that apoptotic cell death and ER stress are increased in atherosclerotic lesions from mice fed hyperhomocysteinemic diets (Zhou and Austin, submitted), it is possible that homocysteine-induced ER stress could adversely affect the stability and/or thrombogenicity of atherosclerotic lesions.…”

Section: Hhcy Er Stress and Apoptotic Cell Deathmentioning

confidence: 99%

Role of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease

2004

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Hyperhomocysteinemia (HHcy) is an independent risk factor for cardiovascular disease, including ischemic heart disease, stroke, and peripheral vascular disease. Mutations in the enzymes responsible for homocysteine metabolism, particularly cystathionine b-synthase (CBS) or 5,10-methylenetetrahydrofolate reductase (MTHFR), result in severe forms of HHcy. Additionally, nutritional deficiencies in B vitamin cofactors required for homocysteine metabolism, including folic acid, vitamin B6 (pyridoxal phosphate), and/or B12 (methylcobalamin), can induce HHcy. Studies using animal models of genetic-and diet-induced HHcy have recently demonstrated a causal relationship between HHcy, endothelial dysfunction, and accelerated atherosclerosis. Dietary enrichment in B vitamins attenuates these adverse effects of HHcy. Although oxidative stress and activation of proinflammatory factors have been proposed to explain the atherogenic effects of HHcy, recent in vitro and in vivo studies demonstrate that HHcy induces endoplasmic reticulum (ER) stress, leading to activation of the unfolded protein response (UPR). This review summarizes the current role of HHcy in endothelial dysfunction and explores the cellular mechanisms, including ER stress, that contribute to atherothrombosis.

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“…Findings reported in our previous study indicated that Ado-Hcy hydrolase is not involved in HL-60 apoptosis by DZA because other Ado-Hcy inhibitors did not activate apoptosis and did not affect DZA-induced apoptosis [11]. Ado-Met and Hcy were reported to induce apoptosis in human colon cancer and HL-60 cells, respectively [23,24] but, their effective concentrations were above 0.5 mM, which may be such a high level that can be hardly reached by inhibiting Ado-Hcy hydrolase in cells. Thus, it is possible that the apoptosis-inducing activity of DZA may not be related to the inhibition of Ado-Hcy hydrolase but its other characteristics.…”

Section: Discussionmentioning

confidence: 91%

Induction of the Intrinsic Apoptotic Pathway by 3-Deazaadenosine Is Mediated by BAX Activation in HL-60 Cells

Lee

Kang

et al. 2010

Korean J Physiol Pharmacol

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3-Deazaadenosine (DZA), a potent inhibitor of S-adenosylhomocysteine hydrolase, was previously proposed to induce intrinsic apoptosis in human leukemic cells. In the present study, we analyzed the mechanism underlying the DZA-induced intrinsic apoptotic pathway. DZA activated typical caspase-dependent apoptosis in HL-60 cells, as demonstrated by an accumulation of hypo-diploidic cells, the processing of multiple procaspases and an inhibitory effect of z-VAD-Fmk on this cell death. During DZA-induced apoptosis, cytochrome c (cyt c) was released into the cytosol. This was neither prevented by z-VAD-Fmk and nor was it associated with the dissipation of mitochondrial membrane potential (Δ Ψ m). Prior to the release of cyt c, BAX was translocated from the cytosol to mitochondria and underwent oligomerization. Finally, the overexpression of BCL-XL protected HL-60 cells from apoptosis by blocking both the cyt c release and BAX oligomerization. Collectively, these findings suggest that DZA may activate intrinsic apoptosis by stimulating BAX activation and thereby the release of cyt c.

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Homocysteine thiolactone induces apoptotic DNA damage mediated by increased intracellular hydrogen peroxide and caspase 3 activation in HL-60 cells

Cited by 122 publications

References 0 publications

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

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

Role of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease

Induction of the Intrinsic Apoptotic Pathway by 3-Deazaadenosine Is Mediated by BAX Activation in HL-60 Cells

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