Glyceryl trinitrate inhibits hypoxia/reoxygenation-induced apoptosis in the syncytiotrophoblast of the human placenta: therapeutic implications for preeclampsia.
Damage of the placenta resulting from ischemia-reperfusion is important to the pathophysiology of preeclampsia. Here we investigated whether low concentrations of glyceryl trinitrate (GTN), a nitric oxide mimetic with anti-apoptotic properties, inhibit hypoxia/reoxygenation-induced apoptosis in the syncytiotrophoblast of chorionic villous explants from human placentas. Compared with villi analyzed immediately after delivery or maintained under normoxic conditions, villi exposed to a 6-hour cycle of hypoxia/reoxygenation exhibited greater numbers of syncytiotrophoblasts with terminal dUTP nick-end labeling (TUNEL)-positive nuclei in the syncytiotrophoblast. This increased number of TUNEL-positive nuclei was paralleled by higher levels of 4-hydroxynonenal (marker of lipid peroxidation), nitrotyrosine residues, and active caspase-3 and polyADP-ribose polymerase expression. Morphological analysis of explants exposed to hypoxia/reoxygenation revealed apoptotic and aponecrotic features similar to those of chorionic villi from preeclamptic pregnancies. Treatment with GTN during the hy-poxia/reoxygenation cycle blocked the increases in the number of TUNEL-positive nuclei and in the levels of 4-hydroxynonenal, nitrotyrosine, and active caspase-3. Incubation with GTN also attenuated the hypoxia/reoxygenation-induced polyADP-ribose polymerase expression and the apoptotic and aponecrotic morphological alterations. These results suggest that small concentrations of nitric oxide protect chorionic villi from hypoxia/reoxygenation-induced damage and provide a rationale for the use of low doses of nitric oxide mimetics in the treatment and/or prevention of preeclampsia.
Belkacemi
Louiza
L
Department of Anatomy and Cell Biology, Queen's University, Kingston, Ontario, Canada.
Bainbridge
Shannon A
SA
Dickinson
Michelle A
MA
Smith
Graeme N
GN
Graham
Charles H
CH
D000447:Aldehydes / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053148:Caspase 3 / Q000187:drug effects; D024161:Collagen Type XI / Q000187:drug effects; D005260:Female; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D046529:Microscopy, Electron, Transmission; D005996:Nitroglycerin / Q000494:pharmacology*; D009924:Organ Culture Techniques; D011225:Pre-Eclampsia / Q000188:drug therapy*; D011247:Pregnancy; D015427:Reperfusion Injury / Q000517:prevention & control*; D015149:Tocolytic Agents / Q000494:pharmacology*; D014327:Trophoblasts / Q000187:drug effects* / Q000473:pathology; D014443:Tyrosine / Q000031:analogs & derivatives / Q000187:drug effects
D000447:Aldehydes; C499319:COL11A2 protein, human; D024161:Collagen Type XI; D015149:Tocolytic Agents; C002744:3-nitrotyrosine; D014443:Tyrosine; D053148:Caspase 3; D005996:Nitroglycerin; C027576:4-hydroxy-2-nonenal