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The detrimental role of angiotensin receptor agonistic autoantibodies in intrauterine growth restriction seen in preeclampsia.

Irani RA, Zhang Y, Blackwell SC, Zhou CC, Ramin SM, Kellems RE, Xia Y - J. Exp. Med. (2009)

Bottom Line: Recently, emerging evidence indicates that preeclamptic women harbor AT(1) receptor agonistic autoantibodies (AT(1)-AAs) that contribute to the disease features.Thus, these studies identify AT(1)-AA as a novel causative factor of preeclampsia-associated IUGR and offer two possible underlying mechanisms: a direct detrimental effect on fetal development by crossing the placenta and entering fetal circulation, and indirectly through AT(1)-AA-induced placental damage.Our findings highlight AT(1)-AAs as important therapeutic targets.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, Houston, TX, 77030, USA.

ABSTRACT
Growth-restricted fetuses are at risk for a variety of lifelong medical conditions. Preeclampsia, a life-threatening hypertensive disorder of pregnancy, is associated with fetuses who suffer from intrauterine growth restriction (IUGR). Recently, emerging evidence indicates that preeclamptic women harbor AT(1) receptor agonistic autoantibodies (AT(1)-AAs) that contribute to the disease features. However, the exact role of AT(1)-AAs in IUGR and the underlying mechanisms have not been identified. We report that these autoantibodies are present in the cord blood of women with preeclampsia and retain the ability to activate AT(1) receptors. Using an autoantibody-induced animal model of preeclampsia, we show that AT(1)-AAs cross the mouse placenta, enter fetal circulation, and lead to small fetuses with organ growth retardation. AT(1)-AAs also induce apoptosis in the placentas of pregnant mice, human villous explants, and human trophoblast cells. Finally, autoantibody-induced IUGR and placental apoptosis are diminished by either losartan or an autoantibody-neutralizing peptide. Thus, these studies identify AT(1)-AA as a novel causative factor of preeclampsia-associated IUGR and offer two possible underlying mechanisms: a direct detrimental effect on fetal development by crossing the placenta and entering fetal circulation, and indirectly through AT(1)-AA-induced placental damage. Our findings highlight AT(1)-AAs as important therapeutic targets.

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AT1 receptor activation increases trophoblast cell apoptosis. AT1 receptor activation induces apoptosis in HTR-8/SVneo cells, a human trophoblast cell line. (A–C) HTR-8/SVneo cells cultured with IgG derived from preeclamptic patients demonstrate increased apoptosis as compared with explants incubated with IgG derived from normotensive sera. A cell death index (A) based on TUNEL-stained HTR-8/SVneo cells (B) indicates that AT1 receptor activation increases apoptosis. Caspase 3 activity (C) is also increased in HTR-8/SVneo cells cultured with IgG from preeclamptic patients as compared with those cultured with IgG from normotensive patients. Coincubation of PE IgG with losartan or 7-aa epitope peptide reduces the amount of apoptosis as well as caspase 3 activity (green, TUNEL+; blue, DAPI nuclear stain; n = 12 for each variable in three independent experiments). Data are expressed as means ± SEM. *, P < 0.05 versus normotensive IgG treatment; **, P < 0.05 versus preeclamptic IgG treatment. NT, normotensive; PE, preeclampsia. Bars, 500 µm.
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fig6: AT1 receptor activation increases trophoblast cell apoptosis. AT1 receptor activation induces apoptosis in HTR-8/SVneo cells, a human trophoblast cell line. (A–C) HTR-8/SVneo cells cultured with IgG derived from preeclamptic patients demonstrate increased apoptosis as compared with explants incubated with IgG derived from normotensive sera. A cell death index (A) based on TUNEL-stained HTR-8/SVneo cells (B) indicates that AT1 receptor activation increases apoptosis. Caspase 3 activity (C) is also increased in HTR-8/SVneo cells cultured with IgG from preeclamptic patients as compared with those cultured with IgG from normotensive patients. Coincubation of PE IgG with losartan or 7-aa epitope peptide reduces the amount of apoptosis as well as caspase 3 activity (green, TUNEL+; blue, DAPI nuclear stain; n = 12 for each variable in three independent experiments). Data are expressed as means ± SEM. *, P < 0.05 versus normotensive IgG treatment; **, P < 0.05 versus preeclamptic IgG treatment. NT, normotensive; PE, preeclampsia. Bars, 500 µm.

Mentions: Many studies report that human trophoblast cells house the full machinery for apoptotic cell death (Allaire et al., 2000; Huppertz et al., 2006; Kadyrov et al., 2006). They also possess the AT1 receptor (Li et al., 1998; Xia et al., 2002). To further elucidate the mechanism by which cell death may occur in the placenta of a preeclamptic woman, we monitored the levels of apoptosis in trophoblasts after stimulation with IgG purified from preeclamptic or normotensive pregnant individuals. Interestingly, IgG purified from preeclamptic individuals induced an increase in programmed cell death in an immortalized human trophoblast line, HTR-8/SVneo (Fig. 6, A and B). This is in contrast to IgG from normotensive pregnant women, which did not raise the level of apoptosis as assessed by a TUNEL assay and apoptotic index. These findings reveal that AT1 receptor activation is capable of inducing apoptosis in trophoblast cells. Consistent with the findings in mouse placental sections and human placental villous explants, we found that the increased apoptosis in the human trophoblast cells by AT1-AAs was inhibited by coincubation with losartan or the 7-aa epitope peptide (Fig. 6, A and B). In addition, the activity of caspase 3, a rapidly activated cysteine protease essential for cell death, was measured in the cultured trophoblast cells to corroborate the TUNEL assay results. HTR-8/SVneo cells incubated with IgG from preeclamptic women exhibited a higher caspase 3 activity level over those incubated with IgG isolated from normotensive pregnant women (Fig. 6 C). The coincubation of the cultured trophoblast cells with AT1-AAs and losartan or the 7-aa epitope peptide reduced the caspase 3 activity significantly. These data support the findings obtained from the human placental villous explants that demonstrate increased apoptosis when exposed to the autoantibody (Fig. 5). Overall, these results provide strong in vitro evidence that autoantibodies isolated from the sera of preeclamptic women are capable of activating AT1 receptors on human trophoblast cells and inducing their programmed cell death.


The detrimental role of angiotensin receptor agonistic autoantibodies in intrauterine growth restriction seen in preeclampsia.

Irani RA, Zhang Y, Blackwell SC, Zhou CC, Ramin SM, Kellems RE, Xia Y - J. Exp. Med. (2009)

AT1 receptor activation increases trophoblast cell apoptosis. AT1 receptor activation induces apoptosis in HTR-8/SVneo cells, a human trophoblast cell line. (A–C) HTR-8/SVneo cells cultured with IgG derived from preeclamptic patients demonstrate increased apoptosis as compared with explants incubated with IgG derived from normotensive sera. A cell death index (A) based on TUNEL-stained HTR-8/SVneo cells (B) indicates that AT1 receptor activation increases apoptosis. Caspase 3 activity (C) is also increased in HTR-8/SVneo cells cultured with IgG from preeclamptic patients as compared with those cultured with IgG from normotensive patients. Coincubation of PE IgG with losartan or 7-aa epitope peptide reduces the amount of apoptosis as well as caspase 3 activity (green, TUNEL+; blue, DAPI nuclear stain; n = 12 for each variable in three independent experiments). Data are expressed as means ± SEM. *, P < 0.05 versus normotensive IgG treatment; **, P < 0.05 versus preeclamptic IgG treatment. NT, normotensive; PE, preeclampsia. Bars, 500 µm.
© Copyright Policy - openaccess
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC2806612&req=5

fig6: AT1 receptor activation increases trophoblast cell apoptosis. AT1 receptor activation induces apoptosis in HTR-8/SVneo cells, a human trophoblast cell line. (A–C) HTR-8/SVneo cells cultured with IgG derived from preeclamptic patients demonstrate increased apoptosis as compared with explants incubated with IgG derived from normotensive sera. A cell death index (A) based on TUNEL-stained HTR-8/SVneo cells (B) indicates that AT1 receptor activation increases apoptosis. Caspase 3 activity (C) is also increased in HTR-8/SVneo cells cultured with IgG from preeclamptic patients as compared with those cultured with IgG from normotensive patients. Coincubation of PE IgG with losartan or 7-aa epitope peptide reduces the amount of apoptosis as well as caspase 3 activity (green, TUNEL+; blue, DAPI nuclear stain; n = 12 for each variable in three independent experiments). Data are expressed as means ± SEM. *, P < 0.05 versus normotensive IgG treatment; **, P < 0.05 versus preeclamptic IgG treatment. NT, normotensive; PE, preeclampsia. Bars, 500 µm.
Mentions: Many studies report that human trophoblast cells house the full machinery for apoptotic cell death (Allaire et al., 2000; Huppertz et al., 2006; Kadyrov et al., 2006). They also possess the AT1 receptor (Li et al., 1998; Xia et al., 2002). To further elucidate the mechanism by which cell death may occur in the placenta of a preeclamptic woman, we monitored the levels of apoptosis in trophoblasts after stimulation with IgG purified from preeclamptic or normotensive pregnant individuals. Interestingly, IgG purified from preeclamptic individuals induced an increase in programmed cell death in an immortalized human trophoblast line, HTR-8/SVneo (Fig. 6, A and B). This is in contrast to IgG from normotensive pregnant women, which did not raise the level of apoptosis as assessed by a TUNEL assay and apoptotic index. These findings reveal that AT1 receptor activation is capable of inducing apoptosis in trophoblast cells. Consistent with the findings in mouse placental sections and human placental villous explants, we found that the increased apoptosis in the human trophoblast cells by AT1-AAs was inhibited by coincubation with losartan or the 7-aa epitope peptide (Fig. 6, A and B). In addition, the activity of caspase 3, a rapidly activated cysteine protease essential for cell death, was measured in the cultured trophoblast cells to corroborate the TUNEL assay results. HTR-8/SVneo cells incubated with IgG from preeclamptic women exhibited a higher caspase 3 activity level over those incubated with IgG isolated from normotensive pregnant women (Fig. 6 C). The coincubation of the cultured trophoblast cells with AT1-AAs and losartan or the 7-aa epitope peptide reduced the caspase 3 activity significantly. These data support the findings obtained from the human placental villous explants that demonstrate increased apoptosis when exposed to the autoantibody (Fig. 5). Overall, these results provide strong in vitro evidence that autoantibodies isolated from the sera of preeclamptic women are capable of activating AT1 receptors on human trophoblast cells and inducing their programmed cell death.

Bottom Line: Recently, emerging evidence indicates that preeclamptic women harbor AT(1) receptor agonistic autoantibodies (AT(1)-AAs) that contribute to the disease features.Thus, these studies identify AT(1)-AA as a novel causative factor of preeclampsia-associated IUGR and offer two possible underlying mechanisms: a direct detrimental effect on fetal development by crossing the placenta and entering fetal circulation, and indirectly through AT(1)-AA-induced placental damage.Our findings highlight AT(1)-AAs as important therapeutic targets.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, Houston, TX, 77030, USA.

ABSTRACT
Growth-restricted fetuses are at risk for a variety of lifelong medical conditions. Preeclampsia, a life-threatening hypertensive disorder of pregnancy, is associated with fetuses who suffer from intrauterine growth restriction (IUGR). Recently, emerging evidence indicates that preeclamptic women harbor AT(1) receptor agonistic autoantibodies (AT(1)-AAs) that contribute to the disease features. However, the exact role of AT(1)-AAs in IUGR and the underlying mechanisms have not been identified. We report that these autoantibodies are present in the cord blood of women with preeclampsia and retain the ability to activate AT(1) receptors. Using an autoantibody-induced animal model of preeclampsia, we show that AT(1)-AAs cross the mouse placenta, enter fetal circulation, and lead to small fetuses with organ growth retardation. AT(1)-AAs also induce apoptosis in the placentas of pregnant mice, human villous explants, and human trophoblast cells. Finally, autoantibody-induced IUGR and placental apoptosis are diminished by either losartan or an autoantibody-neutralizing peptide. Thus, these studies identify AT(1)-AA as a novel causative factor of preeclampsia-associated IUGR and offer two possible underlying mechanisms: a direct detrimental effect on fetal development by crossing the placenta and entering fetal circulation, and indirectly through AT(1)-AA-induced placental damage. Our findings highlight AT(1)-AAs as important therapeutic targets.

Show MeSH
Related in: MedlinePlus