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Heme oxygenase induction attenuates TNF-α-induced hypertension in pregnant rodents.

George EM, Stout JM, Stec DE, Granger JP - Front Pharmacol (2015)

Bottom Line: HO-1 induction had no effect in control animals, but significantly decreased MAP in TNF-α-infused animals (108 ± 2 mmHg).Placental vascular endothelial growth factor (VEGF) was decreased in response to TNF-α infusion (92 ± 4 vs. 76 ± 2 pg/mg).In contrast, HO-1 induction had no significant effect on placental VEGF in TNF-α-infused animals.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Biophysics, University of Mississippi Medical Center , Jackson, MS, USA ; Department of Biochemistry, University of Mississippi Medical Center , Jackson, MS, USA.

ABSTRACT
Pre-eclampsia is a hypertensive disorder of pregnancy initiated by placental insufficiency and chronic ischemia. In response, several pathways activated in the placenta are responsible for the maternal syndrome, including increased production of the anti-angiogenic protein, sFlt-1, and inflammatory cytokines, especially tumor necrosis factor-alpha (TNF-α). Previous studies have demonstrated that heme oxygenase (HO) induction can block TNF-α pathways in vitro and attenuate placental ischemia-induced sFlt-1 in vivo. Here, we investigated whether HO-1 induction could attenuate TNF-α-induced hypertension in pregnant rats. In response to TNF-α infusion (100 ng/day i.p.), maternal mean arterial pressure (MAP) increased vs. control animals (104 ± 3 vs. 119 ± 3 mmHg). HO-1 induction had no effect in control animals, but significantly decreased MAP in TNF-α-infused animals (108 ± 2 mmHg). Placental vascular endothelial growth factor (VEGF) was decreased in response to TNF-α infusion (92 ± 4 vs. 76 ± 2 pg/mg). Placental sFlt-1 was increased by TNF-α infusion (758 ± 45 vs. 936 ± 46 pg/mg, p < 0.05), which trended to normalization by HO-1 induction (779 ± 98 pg/mg). In contrast, HO-1 induction had no significant effect on placental VEGF in TNF-α-infused animals. Taken together, these data suggest that one of the key mechanisms by which HO exerts cytoprotective actions in the placenta during inflammation due to chronic ischemia is through suppression of sFlt-1. Further work elucidating the bioactive metabolites of HO-1 in innate inflammatory responses to placental ischemia is warranted.

No MeSH data available.


Related in: MedlinePlus

(A) In response to TNF-α infusion, mean arterial pressure was significantly elevated compared to normal pregnant controls. Administration of CoPP had no significant effect on mean pressure in normal pregnant animals, but significantly reduced the mean pressure in animals infused with TNF-α. There was no significant effect of either TNF-α infusion or CoPP treatment on either fetal weight (B) or placental mass (C). Statistical significance at p < 0.05 is indicated by connecting lines. Level of significance is indicated by asterisks (*p < 0.05, **p < 0.005).
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Figure 2: (A) In response to TNF-α infusion, mean arterial pressure was significantly elevated compared to normal pregnant controls. Administration of CoPP had no significant effect on mean pressure in normal pregnant animals, but significantly reduced the mean pressure in animals infused with TNF-α. There was no significant effect of either TNF-α infusion or CoPP treatment on either fetal weight (B) or placental mass (C). Statistical significance at p < 0.05 is indicated by connecting lines. Level of significance is indicated by asterisks (*p < 0.05, **p < 0.005).

Mentions: After 5 days of continuous infusion of TNF-α (Figure 2A), pregnant dams exhibited a significant 15-mmHg increase (104 ± 3 vs. 119 ± 3 mmHg, p < 0.005) in mean arterial pressure (MAP). While administration of the HO-1 inducer CoPP had no effect on control animals (104 ± 3 vs. 105 ± 3 mmHg), it significantly attenuated the rise in blood pressure caused by infusion of TNF-α (119 ± 3 vs. 108 ± 2 mmHg, p < 0.05). These data suggest that induction of HO-1 has no effect on blood pressure under normal conditions in pregnant rats, but blocks the hypertensive effects of TNF-α during pregnancy. In line with other published data in pregnant rodents, there was no effect of HO-1 induction on either fetal or placental mass (Figures 2B,C).


Heme oxygenase induction attenuates TNF-α-induced hypertension in pregnant rodents.

George EM, Stout JM, Stec DE, Granger JP - Front Pharmacol (2015)

(A) In response to TNF-α infusion, mean arterial pressure was significantly elevated compared to normal pregnant controls. Administration of CoPP had no significant effect on mean pressure in normal pregnant animals, but significantly reduced the mean pressure in animals infused with TNF-α. There was no significant effect of either TNF-α infusion or CoPP treatment on either fetal weight (B) or placental mass (C). Statistical significance at p < 0.05 is indicated by connecting lines. Level of significance is indicated by asterisks (*p < 0.05, **p < 0.005).
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4538306&req=5

Figure 2: (A) In response to TNF-α infusion, mean arterial pressure was significantly elevated compared to normal pregnant controls. Administration of CoPP had no significant effect on mean pressure in normal pregnant animals, but significantly reduced the mean pressure in animals infused with TNF-α. There was no significant effect of either TNF-α infusion or CoPP treatment on either fetal weight (B) or placental mass (C). Statistical significance at p < 0.05 is indicated by connecting lines. Level of significance is indicated by asterisks (*p < 0.05, **p < 0.005).
Mentions: After 5 days of continuous infusion of TNF-α (Figure 2A), pregnant dams exhibited a significant 15-mmHg increase (104 ± 3 vs. 119 ± 3 mmHg, p < 0.005) in mean arterial pressure (MAP). While administration of the HO-1 inducer CoPP had no effect on control animals (104 ± 3 vs. 105 ± 3 mmHg), it significantly attenuated the rise in blood pressure caused by infusion of TNF-α (119 ± 3 vs. 108 ± 2 mmHg, p < 0.05). These data suggest that induction of HO-1 has no effect on blood pressure under normal conditions in pregnant rats, but blocks the hypertensive effects of TNF-α during pregnancy. In line with other published data in pregnant rodents, there was no effect of HO-1 induction on either fetal or placental mass (Figures 2B,C).

Bottom Line: HO-1 induction had no effect in control animals, but significantly decreased MAP in TNF-α-infused animals (108 ± 2 mmHg).Placental vascular endothelial growth factor (VEGF) was decreased in response to TNF-α infusion (92 ± 4 vs. 76 ± 2 pg/mg).In contrast, HO-1 induction had no significant effect on placental VEGF in TNF-α-infused animals.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Biophysics, University of Mississippi Medical Center , Jackson, MS, USA ; Department of Biochemistry, University of Mississippi Medical Center , Jackson, MS, USA.

ABSTRACT
Pre-eclampsia is a hypertensive disorder of pregnancy initiated by placental insufficiency and chronic ischemia. In response, several pathways activated in the placenta are responsible for the maternal syndrome, including increased production of the anti-angiogenic protein, sFlt-1, and inflammatory cytokines, especially tumor necrosis factor-alpha (TNF-α). Previous studies have demonstrated that heme oxygenase (HO) induction can block TNF-α pathways in vitro and attenuate placental ischemia-induced sFlt-1 in vivo. Here, we investigated whether HO-1 induction could attenuate TNF-α-induced hypertension in pregnant rats. In response to TNF-α infusion (100 ng/day i.p.), maternal mean arterial pressure (MAP) increased vs. control animals (104 ± 3 vs. 119 ± 3 mmHg). HO-1 induction had no effect in control animals, but significantly decreased MAP in TNF-α-infused animals (108 ± 2 mmHg). Placental vascular endothelial growth factor (VEGF) was decreased in response to TNF-α infusion (92 ± 4 vs. 76 ± 2 pg/mg). Placental sFlt-1 was increased by TNF-α infusion (758 ± 45 vs. 936 ± 46 pg/mg, p < 0.05), which trended to normalization by HO-1 induction (779 ± 98 pg/mg). In contrast, HO-1 induction had no significant effect on placental VEGF in TNF-α-infused animals. Taken together, these data suggest that one of the key mechanisms by which HO exerts cytoprotective actions in the placenta during inflammation due to chronic ischemia is through suppression of sFlt-1. Further work elucidating the bioactive metabolites of HO-1 in innate inflammatory responses to placental ischemia is warranted.

No MeSH data available.


Related in: MedlinePlus