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Induction of heme oxygenase 1 attenuates placental ischemia-induced hypertension.

Abstract
Recent in vitro studies have reported that heme oxygenase 1 (HO-1) downregulates the angiostatic protein soluble fms-like tyrosine kinase 1 from placental villous explants and that the HO-1 metabolites CO and bilirubin negatively regulate endothelin 1 and reactive oxygen species. Although soluble fms-like tyrosine kinase 1, endothelin 1, and reactive oxygen species have been implicated in the pathophysiology of hypertension during preeclampsia and in response to placental ischemia in pregnant rats, it is unknown whether chronic induction of HO-1 alters the hypertensive response to placental ischemia. The present study examined the hypothesis that HO-1 induction in a rat model of placental ischemia would beneficially affect blood pressure, angiogenic balance, superoxide, and endothelin 1 production in the ischemic placenta. To achieve this goal we examined the effects of cobalt protoporphyrin, an HO-1 inducer, in the reduced uterine perfusion pressure (RUPP) placental ischemia model and in normal pregnant rats. In response to RUPP treatment, mean arterial pressure increases 29 mm Hg (136±7 versus 106±5 mm Hg), which is significantly attenuated by cobalt protoporphyrin (118±5 mm Hg). Although RUPP treatment causes placental soluble fms-like tyrosine kinase 1/vascular endothelial growth factor ratios to alter significantly to an angiostatic balance (1.00±0.10 versus 1.27±0.20), treatment with cobalt protoporphyrin causes a significant shift in the ratio to an angiogenic balance (0.68±0.10). Placental superoxide increased in RUPP (952.5±278.8 versus 243.9±70.5 relative light units/min per milligram) but was significantly attenuated by HO-1 induction (482.7±117.4 relative light units/min per milligram). Also, the preproendothelin message was significantly increased in RUPP, which was prevented by cobalt protoporphyrin. These data indicate that HO-1, or its metabolites, is a potential therapeutic for the treatment of preeclampsia.
AuthorsEric M George, Kathy Cockrell, Marietta Aranay, Eva Csongradi, David E Stec, Joey P Granger
JournalHypertension (Dallas, Tex. : 1979) (Hypertension) Vol. 57 Issue 5 Pg. 941-8 (May 2011) ISSN: 1524-4563 [Electronic] United States
PMID21383306 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Protoporphyrins
  • Reactive Oxygen Species
  • Vascular Endothelial Growth Factor A
  • cobaltiprotoporphyrin
  • Heme Oxygenase-1
  • Vascular Endothelial Growth Factor Receptor-1
Topics
  • Animals
  • Blood Pressure (physiology)
  • Blotting, Western
  • Female
  • Heme Oxygenase-1 (metabolism)
  • Hypertension (enzymology, etiology, physiopathology)
  • Ischemia (complications, enzymology, physiopathology)
  • Placenta (blood supply, drug effects, enzymology, physiopathology)
  • Pregnancy
  • Protoporphyrins (pharmacology)
  • Rats
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species (metabolism)
  • Reverse Transcriptase Polymerase Chain Reaction
  • Uterus (blood supply, drug effects, enzymology, physiopathology)
  • Vascular Endothelial Growth Factor A (metabolism)
  • Vascular Endothelial Growth Factor Receptor-1 (metabolism)

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