Glyceryl trinitrate inhibits hypoxia/reoxygenation-induced apoptosis in the syncytiotrophoblast of the human placenta: therapeutic implications for preeclampsia.

Abstract

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.

• Authors: Louiza Belkacemi, Shannon A Bainbridge, Michelle A Dickinson, Graeme N Smith, Charles H Graham
• Journal: The American journal of pathology (Am J Pathol) Vol. 170 Issue 3 Pg. 909-20 (Mar 2007) ISSN: 0002-9440 [Print] United States
• PMID: 17322376 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aldehydes
• COL11A2 protein, human
• Collagen Type XI
• Tocolytic Agents
• 3-nitrotyrosine
• Tyrosine
• Caspase 3
• Nitroglycerin
• 4-hydroxy-2-nonenal

Topics

• Aldehydes (metabolism)
• Apoptosis (drug effects)
• Blotting, Western
• Caspase 3 (drug effects)
• Collagen Type XI (drug effects)
• Female
• Humans
• Hypoxia (physiopathology)
• Immunohistochemistry
• In Situ Nick-End Labeling
• Microscopy, Electron, Transmission
• Nitroglycerin (pharmacology)
• Organ Culture Techniques
• Pre-Eclampsia (drug therapy)
• Pregnancy
• Reperfusion Injury (prevention & control)
• Tocolytic Agents (pharmacology)
• Trophoblasts (drug effects, pathology)
• Tyrosine (analogs & derivatives, drug effects)