Agonistic angiotensin II type 1 receptor autoantibodies in postpartum women with a history of preeclampsia

Activating angiotensin II type 1 autoantibodies (AT1-AAs) develop in women with preeclampsia and may contribute to the disorder. Insulin resistance and serum concentrations of the antiangiogenic soluble fms-like tyrosine kinase 1 (sFlt-1) are also increased in women with preeclampsia compared with normal pregnancy. sFlt-1 and insulin resistance decrease substantially after delivery; however, significant group differences persist postpartum. Women who have had preeclampsia are at increased cardiovascular risk later in life. We measured AT1-AAs in groups of women with previous preeclampsia (n=29) and previous normal pregnancies (n=35) 18+/-9 months after the first completed pregnancy. These women had had sFlt-1, insulin resistance homeostasis model assessment score, and related cardiovascular risk factors measured. Activating antibodies were detected by the chronotropic response of cultured neonatal rat cardiomyocytes coupled with receptor-specific antagonists (losartan and prazosin). AT1-AAs were detected in 17.2% of women with previous preeclampsia versus 2.9% of women with previous uncomplicated pregnancies (P<0.05). In contrast, there was no difference in the prevalence of autoantibodies against the alpha1-adrenoceptor (10% of previous preeclamptic versus 14% of previous normal pregnant). Women with activating autoantibodies had significantly increased sFlt-1, reduced free vascular endothelial growth factor, and higher insulin resistance homeostasis model assessment values compared with autoantibody-negative women. These data suggest that, as with sFlt-1 and insulin resistance, the AT1-AA does not regress completely after delivery and, secondarily, that correlations exist among these variables. The impact of AT1-AA after preeclampsia, especially in the context of cardiovascular risk, remains to be determined

Role of lipid peroxidation and the glutathione-dependent antioxidant system in the impairment of endothelium-dependent relaxations with age

1. Age-related changes in the blood prooxidant-antioxidant state, as well as its influence on the relaxant responses to acetylcholine (ACh) were studied in the tail artery from 6-, 24- and 30-month-old Sprague-Dawley (SD) rats. 2. Malondialdehyde (MDA) plasma levels increased 2 and 3 times in 24- and 30-month-old rats, respectively, when compared with 6-month-old rats (0.43±0.09 μM). This increase was accompanied by an induction of 6-phosphogluconate dehydrogenase (6PG-DH) and glutathione reductase (GR) activities in red blood cells from 24-month-old rats. In 30-month-old rats, a further induction of these enzymatic activities, as well as glucose-6-phosphate dehydrogenase (G6P-DH) and glutathione peroxidase (GPx) activities was observed. 3. No differences with age were found in the concentration-response curves to ACh in isolated tail artery segments from 6- and 24-month-old rats precontracted with 0.3 μM noradrenaline (NA). However, a decrease in sensitivity to ACh-induced relaxation was observed in 30-month-old rats; EC(30) values were 3.5 (1.3–8.0)×10(−7) M and 18.1 (8.9–30.1)×10(−7) M for 6- and 30-month-old rats, respectively. Moreover, a decrease in maximum ACh relaxation (10 μM) was found in 30-month-old rats in comparison with that obtained in 6-month-old rats (58.5±3.9% and 42.5±3.4% of previous NA contraction, respectively). 4. Incubation of tail artery segments with MDA (0.5, 1 or 10 μM) caused a reduction of ACh-induced relaxations that was different in the three ages. Thus, the reduction of ACh-induced relaxations became significant with 0.5 μM MDA in 6-, with 1 μM MDA in 24-, and with 10 μM MDA in 30-month-old rats. In addition, MDA did not cause a shift in the concentration-response curve to ACh, but a decrease in the maximum response. 5. Superoxide dismutase (SOD; 150 u ml(−1), a superoxide anion scavenger) reversed the inhibitory effect of MDA on ACh-induced relaxations at all ages studied. 6. We conclude that: (1) ageing produces an increase in lipid peroxidation process, as indicated by the increase in MDA plasma levels, that is accompanied by an induction of lipid peroxide detoxification enzymes; (2) the changes in prooxidant-antioxidant equilibrium with age contribute, at least partially, to the impairment of the relaxant responses evoked by ACh; and (3) the effect of MDA appears to be mediated by superoxide anion at all ages studied

Spin, quadrupole moment, and deformation of the magnetic-rotational band head in Pb-193

he spectroscopic quadrupole moment of the T-1/2 = 9.4(5) ns isomer in Pb-193 at an excitation energy E-ex = (2585 + x) keV is measured by the time-differential perturbed angular distribution method as vertical bar Q(s)vertical bar = 2.6(3) e b. Spin and parity I-pi = 27/2(-) are assigned to it based on angular distribution measurements. This state is the band head of a magnetic-rotational band, described by the coupling of a neutron hole in the 1i(13/2) subshell with the (3s(1/2)(-2)1h(9/2)1i(13/2))(11-) proton excitation. The pairing-plus-quadrupole tilted-axis cranking calculations reproduce the measured quadrupole moment with a moderate oblate deformation epsilon(2) = -0.11, similar to that of the 11(-)proton intruder states, which occur in the even-even Pb nuclei in the region. This is the first direct measurement of a quadrupole moment and thus of the deformation of a magnetic-rotational band head

Angiotensin II type 1 receptor antibodies and increased angiotensin II sensitivity in pregnant rats

Pregnant women who subsequently develop preeclampsia are highly sensitive to infused angiotensin (Ang) II; the sensitivity persists postpartum. Activating autoantibodies against the Ang II type 1 (AT(1)) receptor are present in preeclampsia. In vitro and in vivo data suggest that they could be involved in the disease process. We generated and purified activating antibodies against the AT(1) receptor (AT(1)-AB) by immunizing rabbits against the AFHYESQ epitope of the second extracellular loop, which is the binding epitope of endogenous activating autoantibodies against AT(1) from patients with preeclampsia. We then purified AT(1)-AB using affinity chromatography with the AFHYESQ peptide. We were able to detect AT(1)-AB both by ELISA and a functional bioassay. We then passively transferred AT(1)-AB into pregnant rats, alone or combined with Ang II. AT(1)-AB activated protein kinase C-α and extracellular-related kinase 1/2. Passive transfer of AT(1)-AB alone or Ang II (435 ng/kg per minute) infused alone did not induce a preeclampsia-like syndrome in pregnant rats. However, the combination (AT(1)-AB plus Ang II) induced hypertension, proteinuria, intrauterine growth retardation, and arteriolosclerosis in the uteroplacental unit. We next performed gene-array profiling of the uteroplacental unit and found that hypoxia-inducible factor 1α was upregulated by Ang II plus AT(1)-AB, which we then confirmed by Western blotting in villous explants. Furthermore, endothelin 1 was upregulated in endothelial cells by Ang II plus AT(1)-AB. We show that AT(1)-AB induces Ang II sensitivity. Our mechanistic study supports the existence of an "autoimmune-activating receptor" that could contribute to Ang II sensitivity and possible to preeclampsia