S -Adenosylhomocysteine induces apoptosis and phosphatidylserine exposure in endothelial cells independent of homocysteine

Abstract Objective We have previously shown that homocysteine (Hcy) induces phosphatidylserine (PS) exposure, apoptosis and necrosis in human endothelial cells. Since it has been suggested that S -Adenosylhomocysteine (SAH) is the main causative factor in Hcy-induced pathogenesis of cardiovascular d...

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Published in:Atherosclerosis 2012-03, Vol.221 (1), p.48-54
Main Authors: Sipkens, Jessica A, Hahn, Nynke E, Blom, Henk J, Lougheed, Sinéad M, Stehouwer, Coen D.A, Rauwerda, Jan A, Krijnen, Paul A.J, van Hinsbergh, Victor W.M, Niessen, Hans W.M
Format: Article
Language:English
Subjects:
Adenosine - analogs & derivatives
Adenosine - pharmacology
apoptosis
Apoptosis - drug effects
atherosclerosis
Atherosclerosis (general aspects, experimental research)
Biological and medical sciences
Blood and lymphatic vessels
Blood vessels and receptors
Cardiology. Vascular system
Cardiovascular
Caspase 3 - metabolism
caspase-3
Cell Survival
cell viability
Cells, Cultured
cytochrome c
Cytochromes c - metabolism
cytotoxicity
Endothelial cells
Endothelial Cells - drug effects
Endothelial Cells - metabolism
Endothelial Cells - pathology
Enzyme Inhibitors - pharmacology
Fundamental and applied biological sciences. Psychology
Homocysteine
Homocysteine - metabolism
human umbilical vein endothelial cells
Humans
hydrogen peroxide
Hydrogen Peroxide - metabolism
Medical sciences
Membrane Glycoproteins - antagonists & inhibitors
Membrane Glycoproteins - metabolism
NADPH oxidase
NADPH Oxidase 2
NADPH Oxidase 4
NADPH Oxidases - antagonists & inhibitors
NADPH Oxidases - metabolism
necrosis
Onium Compounds - pharmacology
pathogenesis
Phosphatidylserines - metabolism
S-Adenosylhomocysteine
S-Adenosylhomocysteine - metabolism
Tyrosine - analogs & derivatives
Tyrosine - metabolism
Vertebrates: cardiovascular system
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Summary:Abstract Objective We have previously shown that homocysteine (Hcy) induces phosphatidylserine (PS) exposure, apoptosis and necrosis in human endothelial cells. Since it has been suggested that S -Adenosylhomocysteine (SAH) is the main causative factor in Hcy-induced pathogenesis of cardiovascular disease, we evaluate here whether the cytotoxic Hcy effect in endothelial cells is also SAH dependent. Methods and results Human umbilical vein endothelial cells (HUVECs) were exposed to the following conditions: (1) non-treated control (resulting in 2.8 nM intracellular SAH and 3.1 μM extracellular l -Hcy); and incubation with (2) 50 μM adenosine-2,3-dialdehyde (ADA; resulting in 17.7 nM intracellular SAH and 3.1 μM extracellular l -Hcy), (3) 2.5 mM Hcy (resulting in 20.9 nM intracellular SAH and 1.8 mM extracellular l -Hcy), and (4) 1, 10 and 100 μM SAH. We then determined the effect of treatment on annexin V-positivity, caspase-3 activity, cytochrome c release (sub)cellular expression of NOX2, NOX4, p47phox and nitrotyrosine, and H2 O2 . Both Hcy and ADA significantly increased PS exposure ( n = 5), caspase-3 activity ( n = 6) and cytochrome c release ( n = 3). Incubation with extracellular SAH alone did not affect cell viability. Both Hcy and ADA also induced similar increases in nuclear NOX2 and (peri)nuclear NOX4, coinciding with (peri)nuclear p47phox expression and local reactive oxygen species (ROS) ( n = 3). Inhibition of NOX-mediated ROS by the flavoenzyme inhibitor diphenylene iodonium (DPI) significantly decreased apoptosis induction ( n = 3) and ROS production ( n = 3). Conclusion SAH induces PS exposure and apoptosis in endothelial cells independently of Hcy. Our study therefore shows that Hcy-mediated endothelial dysfunction, as determined in the cell model used, is mainly due to SAH accumulation.
ISSN:0021-9150
1879-1484
DOI:10.1016/j.atherosclerosis.2011.11.032