Limits...
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

Circulating plasma TNF-α levels were determined by ELISA (A). In response to continuous i.p. TNF-α infusion (TNF), plasma levels were elevated in both normal pregnant (NP) and CoPP-treated animals. There was no statistical difference in circulating TNF-α levels between control or CoPP-treated animals. Statistical significance at p < 0.05 is indicated by connecting lines. (B) Liver and placenta (C) heme oxygenase activity was determined in response to TNF-α infusion and CoPP administration. TNF-α infusion alone had no effect on heme oxygenase activity, however, CoPP administration significantly increased HO activity in both control and TNF-α infused animals. Level of significance is indicated by asterisks (*p < 0.05, **p < 0.005).
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4538306&req=5

Figure 1: Circulating plasma TNF-α levels were determined by ELISA (A). In response to continuous i.p. TNF-α infusion (TNF), plasma levels were elevated in both normal pregnant (NP) and CoPP-treated animals. There was no statistical difference in circulating TNF-α levels between control or CoPP-treated animals. Statistical significance at p < 0.05 is indicated by connecting lines. (B) Liver and placenta (C) heme oxygenase activity was determined in response to TNF-α infusion and CoPP administration. TNF-α infusion alone had no effect on heme oxygenase activity, however, CoPP administration significantly increased HO activity in both control and TNF-α infused animals. Level of significance is indicated by asterisks (*p < 0.05, **p < 0.005).

Mentions: To determine whether the administered dose of TNF-α was sufficient to exert a biological effect, plasma levels of the protein were determined via sandwich ELISA. Control animals exhibited low circulating levels of TNF-α (Figure 1A; 3.8 ± 0.2 pg/mL). Animals receiving TNF-α demonstrated a significant ∼50% increase in circulating TNF-α levels (6.1 ± 0.9 pg/mL, p < 0.05). Administration of CoPP had no significant effect on the circulating levels of TNF-α in either control (2.8 ± 0.4 pg/mL) or TNF-α-infused rats (8.4 ± 2.3 pg/mL). Taken together, these data demonstrate that TNF-α infusion increases circulating levels of TNF-α, while CoPP administration has no direct effect. The efficacy of CoPP for induction of HO activity was ascertained by examining HO activity in the livers and placentas of all groups. As seen in Figures 1B,C, TNF alone had no effect on HO activity, but increased HO activity in both control and TNF-infused animals.


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

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

Circulating plasma TNF-α levels were determined by ELISA (A). In response to continuous i.p. TNF-α infusion (TNF), plasma levels were elevated in both normal pregnant (NP) and CoPP-treated animals. There was no statistical difference in circulating TNF-α levels between control or CoPP-treated animals. Statistical significance at p < 0.05 is indicated by connecting lines. (B) Liver and placenta (C) heme oxygenase activity was determined in response to TNF-α infusion and CoPP administration. TNF-α infusion alone had no effect on heme oxygenase activity, however, CoPP administration significantly increased HO activity in both control and TNF-α infused animals. Level of significance is indicated by asterisks (*p < 0.05, **p < 0.005).
© Copyright Policy
Related In: Results  -  Collection

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

Figure 1: Circulating plasma TNF-α levels were determined by ELISA (A). In response to continuous i.p. TNF-α infusion (TNF), plasma levels were elevated in both normal pregnant (NP) and CoPP-treated animals. There was no statistical difference in circulating TNF-α levels between control or CoPP-treated animals. Statistical significance at p < 0.05 is indicated by connecting lines. (B) Liver and placenta (C) heme oxygenase activity was determined in response to TNF-α infusion and CoPP administration. TNF-α infusion alone had no effect on heme oxygenase activity, however, CoPP administration significantly increased HO activity in both control and TNF-α infused animals. Level of significance is indicated by asterisks (*p < 0.05, **p < 0.005).
Mentions: To determine whether the administered dose of TNF-α was sufficient to exert a biological effect, plasma levels of the protein were determined via sandwich ELISA. Control animals exhibited low circulating levels of TNF-α (Figure 1A; 3.8 ± 0.2 pg/mL). Animals receiving TNF-α demonstrated a significant ∼50% increase in circulating TNF-α levels (6.1 ± 0.9 pg/mL, p < 0.05). Administration of CoPP had no significant effect on the circulating levels of TNF-α in either control (2.8 ± 0.4 pg/mL) or TNF-α-infused rats (8.4 ± 2.3 pg/mL). Taken together, these data demonstrate that TNF-α infusion increases circulating levels of TNF-α, while CoPP administration has no direct effect. The efficacy of CoPP for induction of HO activity was ascertained by examining HO activity in the livers and placentas of all groups. As seen in Figures 1B,C, TNF alone had no effect on HO activity, but increased HO activity in both control and TNF-infused animals.

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