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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

Infusion of TNF-α led to a small, but significant, decrease in placental VEGF (A), as did administration of CoPP. There was no statistically significant difference between TNF-α-infused animals with or without CoPP administration. TNF-α infusion was associated with an increase in placental sFlt-1 (B). CoPP had no effect on placental sFlt-1 in normal pregnant animals, but trended to normalization of sFlt-1 levels in TNF-α-infused animals, though this failed to meet significance (p = 0.09). Statistical significance at p < 0.05 is indicated by connecting lines. Level of significance is indicated by asterisks (*p < 0.05).
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Figure 3: Infusion of TNF-α led to a small, but significant, decrease in placental VEGF (A), as did administration of CoPP. There was no statistically significant difference between TNF-α-infused animals with or without CoPP administration. TNF-α infusion was associated with an increase in placental sFlt-1 (B). CoPP had no effect on placental sFlt-1 in normal pregnant animals, but trended to normalization of sFlt-1 levels in TNF-α-infused animals, though this failed to meet significance (p = 0.09). Statistical significance at p < 0.05 is indicated by connecting lines. Level of significance is indicated by asterisks (*p < 0.05).

Mentions: To determine the effects of TNF-α infusion and HO-1 induction on the pro-angiogenic protein VEGF and its antagonist sFlt-1, placental levels of both were determined by sandwich ELISA. Interestingly TNF-α infusion resulted in a decrease in placental VEGF (92 ± 4 vs. 76 ± 2 pg/mg, p < 0.05; Figure 3A), and an increase in placental sFlt-1 (758 ± 45 vs. 936 ± 46 pg/mg, p < 0.05; Figure 3B). In control animals, while HO-1 induction had no significant effect on placental sFlt-1 (Figure 3B); there was significant, decrease in placental VEGF (93 ± 4 vs. 73 ± 7 pg/mg, p < 0.05; Figure 3A). Induction of HO-1 in TNF-α-infused animals likewise had no effect on placental VEGF. There was, however, a strong trend toward normalization of placental sFlt-1 levels, but was not statistically significant (936 ± 46 vs. 779 ± 98 pg/mg, p = 0.09).


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

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

Infusion of TNF-α led to a small, but significant, decrease in placental VEGF (A), as did administration of CoPP. There was no statistically significant difference between TNF-α-infused animals with or without CoPP administration. TNF-α infusion was associated with an increase in placental sFlt-1 (B). CoPP had no effect on placental sFlt-1 in normal pregnant animals, but trended to normalization of sFlt-1 levels in TNF-α-infused animals, though this failed to meet significance (p = 0.09). Statistical significance at p < 0.05 is indicated by connecting lines. Level of significance is indicated by asterisks (*p < 0.05).
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4538306&req=5

Figure 3: Infusion of TNF-α led to a small, but significant, decrease in placental VEGF (A), as did administration of CoPP. There was no statistically significant difference between TNF-α-infused animals with or without CoPP administration. TNF-α infusion was associated with an increase in placental sFlt-1 (B). CoPP had no effect on placental sFlt-1 in normal pregnant animals, but trended to normalization of sFlt-1 levels in TNF-α-infused animals, though this failed to meet significance (p = 0.09). Statistical significance at p < 0.05 is indicated by connecting lines. Level of significance is indicated by asterisks (*p < 0.05).
Mentions: To determine the effects of TNF-α infusion and HO-1 induction on the pro-angiogenic protein VEGF and its antagonist sFlt-1, placental levels of both were determined by sandwich ELISA. Interestingly TNF-α infusion resulted in a decrease in placental VEGF (92 ± 4 vs. 76 ± 2 pg/mg, p < 0.05; Figure 3A), and an increase in placental sFlt-1 (758 ± 45 vs. 936 ± 46 pg/mg, p < 0.05; Figure 3B). In control animals, while HO-1 induction had no significant effect on placental sFlt-1 (Figure 3B); there was significant, decrease in placental VEGF (93 ± 4 vs. 73 ± 7 pg/mg, p < 0.05; Figure 3A). Induction of HO-1 in TNF-α-infused animals likewise had no effect on placental VEGF. There was, however, a strong trend toward normalization of placental sFlt-1 levels, but was not statistically significant (936 ± 46 vs. 779 ± 98 pg/mg, p = 0.09).

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