TY - JOUR
T1 - Homocysteine thiolactone induces apoptosis in cultured human trophoblasts
T2 - A mechanism for homocysteine-mediated placental dysfunction?
AU - Kamudhamas, Atiwut
AU - Pang, Liyi
AU - Smith, Steven D.
AU - Sadovsky, Yoel
AU - Nelson, D. Michael
N1 - Funding Information:
Supported by NIH HD 29190.
PY - 2004/8
Y1 - 2004/8
N2 - Objective Hyperhomocystinemia is a thrombophilic condition associated with placental dysfunction. We tested the hypothesis that homocysteine-thiolactone, a metabolite of homocysteine, induces apoptosis in cultured trophoblasts. Study design Cytotrophoblasts from term human placentas were cultured for 72 hours or less in the presence or absence of 50 to 400 μmol/L homocysteine-thiolactone or 400 μmol/L cysteine (control), with or without vitamin C, vitamin E, folate, or N-acetylcysteine. Cell death was assessed by cellular adenosine triphosphate concentration, medium lactate dehydrogenase level, and immunocytochemical staining for the cleavage products of cytokeratin 18 and poly(adenosine diphosphate ribose) polymerase. Changes in expression of p53, Bcl-2, Bax, and Bak were quantified by Western immunoblotting. Results Homocysteine-thiolactone induced a concentration dependent increase in total cell death and death by apoptosis, compared with control. Vitamin C ameliorated apoptosis in cytotrophoblasts, whereas N-acetylcysteine mitigated cell death in syncytiotrophoblasts. Apoptosis in both phenotypes occurred with increased expression of p53 and Bak, but no change in Bcl-2 or Bax. Conclusion Homocysteine-thiolactone enhances apoptosis in cultured human trophoblast, and the effect can be limited by antioxidants.
AB - Objective Hyperhomocystinemia is a thrombophilic condition associated with placental dysfunction. We tested the hypothesis that homocysteine-thiolactone, a metabolite of homocysteine, induces apoptosis in cultured trophoblasts. Study design Cytotrophoblasts from term human placentas were cultured for 72 hours or less in the presence or absence of 50 to 400 μmol/L homocysteine-thiolactone or 400 μmol/L cysteine (control), with or without vitamin C, vitamin E, folate, or N-acetylcysteine. Cell death was assessed by cellular adenosine triphosphate concentration, medium lactate dehydrogenase level, and immunocytochemical staining for the cleavage products of cytokeratin 18 and poly(adenosine diphosphate ribose) polymerase. Changes in expression of p53, Bcl-2, Bax, and Bak were quantified by Western immunoblotting. Results Homocysteine-thiolactone induced a concentration dependent increase in total cell death and death by apoptosis, compared with control. Vitamin C ameliorated apoptosis in cytotrophoblasts, whereas N-acetylcysteine mitigated cell death in syncytiotrophoblasts. Apoptosis in both phenotypes occurred with increased expression of p53 and Bak, but no change in Bcl-2 or Bax. Conclusion Homocysteine-thiolactone enhances apoptosis in cultured human trophoblast, and the effect can be limited by antioxidants.
KW - Antioxidants
KW - Apoptosis
KW - Homocysteine-thiolactone
KW - Human trophoblasts
KW - Placenta
UR - http://www.scopus.com/inward/record.url?scp=4444305174&partnerID=8YFLogxK
U2 - 10.1016/j.ajog.2004.01.037
DO - 10.1016/j.ajog.2004.01.037
M3 - Article
C2 - 15343238
AN - SCOPUS:4444305174
VL - 191
SP - 563
EP - 571
JO - American Journal of Obstetrics and Gynecology
JF - American Journal of Obstetrics and Gynecology
SN - 0002-9378
IS - 2
ER -