phenanthrenes and Pre-Eclampsia

Preeclampsia (PE) is a serious blood pressure disorder of pregnancy. Systemic endothelial cell dysfunction, a hallmark of PE, is previously estimated to be induced by hypoxic trophoblast high mobility group box 1 (HMGB1). In the present study, we investigated the protective effect of sodium tanshinone IIA sulfonate (STS), the soluble form of tanshinone IIA isolated from danshen, against hypoxic trophoblast HMGB1-induced human umbilical vein endothelial cell (HUVEC) dysfunction. Our results showed that HMGB1 expression and release were significantly decreased in STS-treated hypoxic JEG-3 cells. A further study revealed hypoxic trophoblast HMGB1-induced cytotoxicity and leukostasis of HUVEC as well as higher expression of cell adhesion molecules (VCAM-1 and ICAM-1) could be reversed by pretreatment with STS. In conclusion, our study suggests that STS is an effective agent against hypoxic trophoblast-induced cell injury of HUVEC via targeting HMGB1 release and forms the basis of the development of such a compound in treating PE.

Topics: Cell Hypoxia; Endothelial Cells; Female; Gene Expression Regulation; HMGB1 Protein; Human Umbilical Vein Endothelial Cells; Humans; Phenanthrenes; Pre-Eclampsia; Pregnancy; Trophoblasts

Preeclampsia is a disorder of pregnancy with a significant impact on maternal and fetal health. The complexity of this multifactorial condition has precluded development of effective therapies and, although many potential pathways have been investigated, the etiology still requires clarification. Our group has investigated the scavenger lectin-like oxidized LDL (LOX-1) receptor, which may respond to factors released from the distressed placenta that contribute to the vascular pathologies observed in preeclampsia. Given the known beneficial effects of sodium tanshinone IIA sulfonate (STS; a component of Salvia miltiorrhiza) on vasodilation, reduction of oxidative stress, and lipid profiles, we have investigated its role as a potential treatment strategy. We hypothesized that STS would improve vascular endothelial function and, combined with a reduction in oxidative stress, would improve pregnancy outcomes in a rat model of preeclampsia (reduced uteroplacental perfusion pressure, RUPP). We further hypothesized this may occur via the action of STS on the LOX-1 and/or platelet-activating factor (PAF) receptor axes. The RUPP model increased maternal blood pressure, vascular oxidative stress, and involvement of the vascular PAF receptor. Treatment with STS during pregnancy decreased both oxidative stress and involvement of the PAF receptor; however, it also increased involvement of the LOX-1 receptor, which is in line with the concept that scavenger receptors, such as LOX-1 and PAF, are upregulated in response to ligand binding and/or under pathological conditions. In this model of preeclampsia, however, the vascular actions of STS did not lead to improvements in pregnancy outcome such as fetal biometrics or maternal blood pressure.

Topics: Animals; Blood Pressure; Disease Models, Animal; Endothelium, Vascular; Female; Lipoproteins, LDL; Oxidative Stress; Phenanthrenes; Placenta; Pre-Eclampsia; Pregnancy; Rats, Sprague-Dawley; Vasodilation

Under conditions of increased oxidative stress, such as pre-eclampsia and diabetes, overstimulation of PARP leads to endothelial dysfunction. Inhibition of PARP has been demonstrated to reverse the vascular dysfunction associated with diabetes in vivo. The present study was carried out to investigate the role of PARP in mediating the endothelial dysfunction associated with pre-eclampsia.. Uteroplacental perfusion was surgically reduced in pregnant rats to produce the reduced uterine perfusion pressure (RUPP) rat model of pre-eclampsia and the PARP inhibitor, PJ34, was administered either before or after surgery. Mean arterial BP and vascular function were measured in normal pregnant (NP) and both control and PJ34-treated RUPP rats. Mesenteric vessels from NP rats were incubated with either 3% RUPP or NP plasma alone or in combination with PJ34. Finally, immunohistochemical staining was carried out to measure nitrotyrosine (byproduct of peroxynitrite) immunoreactivity.. RUPP rats were characterized by hypertension, fetal growth restriction and endothelial dysfunction when compared with NP rats. PJ34 administered in vivo before, but not after, surgery prevented the development of both endothelial dysfunction and hypertension. RUPP plasma-induced impaired vasorelaxation was prevented following co-incubation with PJ34 in vitro. Furthermore, the protective effect of PARP inhibition in vivo was accompanied by a reduction in nitrotyrosine immunoreactivity.. PJ34 prevented the development of both endothelial dysfunction and hypertension and reduced vascular nitrotyrosine immunoreactivity, thus suggesting a role for oxidative-nitrosative stress/PARP activation in the aberration in both vascular and haemodynamic function in this rat model of pre-eclampsia.

Topics: Animals; Disease Models, Animal; Endothelium, Vascular; Enzyme Inhibitors; Female; Hypertension; Mesenteric Arteries; Phenanthrenes; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Pre-Eclampsia; Pregnancy; Rats; Rats, Sprague-Dawley

A low-resistance/high-flow uteroplacental circulation is integral to a healthy pregnancy. Impaired flow in the uterine circulation is associated with intrauterine growth restriction (IUGR) and preeclampsia (PE). Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme which has been associated with oxidative stress-induced vascular dysfunction. Using the endothelial nitric oxide synthase (eNOS(-/ -)) knockout mouse model, which features vascular dysfunction and IUGR, we tested the hypothesis that administration of a PARP inhibitor may ameliorate the vascular dysfunction associated with the eNOS(-/-) model. eNOS(-/-) animals were characterized by impaired uterine artery function when compared to controls. Administration of the PARP inhibitor PJ34 prevented this dysfunction. Gestational day (GD) 17.5 eNOS(-/-) mice did not exhibit altered systolic blood pressure when compared to control mice. However, treatment of eNOS(-/-) mice with PJ34 significantly reduced systolic blood pressure when compared to vehicle-treated eNOS(-/-). Administration of a PARP inhibitor protects uterine artery function in the face of eNOS(-/-) deficiency.

Topics: Animals; Enzyme Inhibitors; Female; Fetal Growth Retardation; Gestational Age; Mice; Mice, Inbred C57BL; Mice, Knockout; Nitric Oxide Synthase Type III; Phenanthrenes; Poly(ADP-ribose) Polymerase Inhibitors; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Uterine Artery

1. Pre-eclampsia is a serious pregnancy disorder associated with widespread activation of the maternal vascular endothelium. Recent evidence implicates a role for oxidative stress in the aetiology of this condition. 2. Reactive oxygen species, particularly superoxide anions, invokes endothelial cell activation through many pathways. Oxidant-induced cell injury triggers the activation of nuclear enzyme poly(ADP-ribose) polymerase (PARP) leading to endothelial dysfunction in various pathophysiological conditions (reperfusion, shock, diabetes). 3. We have studied whether the loss of endothelial function in pre-eclampsia is dependent on PARP activity. Endothelium-dependent responses of myometrial arteries were tested following exposure to either plasma from women with pre-eclampsia or normal pregnant women in the presence and absence of a novel potent inhibitor of PARP, PJ34. Additional effects of plasma and PJ34 inhibition were identified in microvascular endothelial cell cultures. 4. In myometrial arteries, PARP inhibition blocked the attenuation of endothelium-dependent responses following exposure to plasma from women with pre-eclampsia. In endothelial cell cultures, plasma from pre-eclamptics induced measurable oxidative stress and a concomitant increase in PARP activity and reduction in cellular ATP. Again, these biochemical changes were reversed by PJ34. 5. These results suggest that PARP activity plays a pathogenic role in the development of endothelial dysfunction in pre-eclampsia and promotes PARP inhibition as a potential therapy in this condition.

Topics: Adenosine Triphosphate; Adult; Animals; Antibodies, Monoclonal; Arteries; Case-Control Studies; Cattle; Cell Survival; Cells, Cultured; Culture Media; Endothelium, Vascular; Enzyme Activation; Enzyme Inhibitors; Female; Humans; L-Lactate Dehydrogenase; Middle Aged; Myometrium; Oxidative Stress; Phenanthrenes; Plasma; Poly(ADP-ribose) Polymerases; Pre-Eclampsia; Pregnancy; Reactive Oxygen Species; Time Factors; Tyrosine