Angiotensin II Type 1 Receptor Autoantibody Research Articles

AT1R autoantibody promotes phenotypic transition of smooth muscle cells by activating AT1R-OAS2

Phenotypic transition of vascular smooth muscle cells (VSMCs) is an early event in the onset and progression of several cardiovascular diseases. As an important mediator of the renin-angiotensin system (RAS), activation of the angiotensin II type 1 receptor (AT1R) induces phenotypic transition of VSMCs. AT1R autoantibodies (AT1-AAs), which are agonistic autoantibodies of AT1R, have been detected in the sera of patients with a variety of cardiovascular diseases associated with phenotypic transition. However, the effect of AT1-AA on phenotypic transition is currently unknown. In this study, AT1-AA-positive rat model was established by active immunization to detect markers of VSMCs phenotypic transition. The results showed that AT1-AA-positive rats showed phenotypic transition of VSMCs, which was evidenced by the decrease of contractile markers, while the increase of synthetic markers in the thoracic aorta. However, in AT1-AA-positive AT1R knockout rats, the phenotypic transition-related proteins were not altered. In vitro, after stimulating human aortic smooth muscle cells with AT1-AA for 48 h, 2′-5′ oligoadenylate synthase 2 (OAS2) was identified as the key differentially expressed gene by RNA sequencing and bioinformatics analysis. Furthermore, high expression of OAS2 was found in aorta of AT1-AA-positive rats; knockdown of OAS2 by siRNA can reverse the phenotypic transition of VSMCs induced by AT1-AA. In summary, this study suggests that AT1-AA can promote phenotypic transition of VSMCs through AT1R-OAS2 pathway, and OAS2 might serve as a potential therapeutic target to prevent pathological phenotypic transition of smooth muscle cells.

Abstract 13769: AT1R Autoantibody Levels Are Elevated in Patients Who Required Immunosuppression Escalation in Immune Checkpoint Inhibitor Mediated Myocarditis

Intro: Angiotensin-II (Ang-II) plays an important role in the pathophysiology of various cardiovascular disorders, including cardiomyopathy and hypertension. Angiotensin II type 1 receptor (AT1R) mediates the deleterious effects of Ang-II and can cause vasoconstriction, vascular and cardiac remodeling, and cell death. Animal models have shown that the AT1R signal is obligatory for the development of virus-induced myocardial injury through the proinflammatory action of Ang-II. Data from animal studies and human case studies showed AT1R autoantibodies (AT1R A) were a novel mediator of vasomotor changes and LV dysfunction related to acute myocarditis and that blocking AT1R can be effective. Hypothesis: Little is known whether patients on immune checkpoint inhibitors (ICI) develop AT1R A and whether this can worsen the severity of ICI myocarditis. We measured AT1R A in 9 hospitalized patients who were diagnosed with ICI induced myocarditis. We describe this cohort, the course of their illness and their response to steroids. Methods: This was a prospective study. Quantitative antibodies to AT1R at the time of hospitalization were measured by an Enzyme Linked Immunosorbent Assay (ELISA) (One Lambda) and classified as positive (>17U/mL); at risk (10-17 U/mL) and negative (<10 U/mL). Results: Demographic and co-morbidity details are shown (Table 1). 5/9 patients (55%) were either positive or at risk for AT1R A elevation. 4/9 patients (45%) were AT1R A negative. 4/5 (80%) of the AT1R A positive/at risk required increased immunosuppression whereas 1/4 (25%) of the AT1R A negative required increased immunosuppression for myocarditis. Conclusions: AT1R autoantibodies may worsen the severity of ICI myocarditis. A larger cohort study and comparisons of AT1R A levels in non-ICI patients are underway. If trends hold true, testing for AT1R A and treating with an angiotensin receptor blocker may be a potential strategy to reduce ICI myocarditis severity.

Preeclampsia: Linking Placental Ischemia with Maternal Endothelial and Vascular Dysfunction.

Preeclampsia (PE), a hypertensive disorder, occurs in 3% to 8% of pregnancies in the United States and affects over 200,000 women and newborns per year. The United States has seen a 25% increase in the incidence of PE, largely owing to increases in risk factors, including obesity and cardiovascular disease. Although the etiology of PE is not clear, it is believed that impaired spiral artery remodeling of the placenta reduces perfusion, leading to placental ischemia. Subsequently, the ischemic placenta releases antiangiogenic and pro-inflammatory factors, such as cytokines, reactive oxygen species, and the angiotensin II type 1 receptor autoantibody (AT1-AA), among others, into the maternal circulation. These factors cause widespread endothelial activation, upregulation of the endothelin system, and vasoconstriction. In turn, these changes affect the function of multiple organ systems including the kidneys, brain, liver, and heart. Despite extensive research into the pathophysiology of PE, the only treatment option remains early delivery of the baby and importantly, the placenta. While premature delivery is effective in ameliorating immediate risk to the mother, mounting evidence suggests that PE increases risk of cardiovascular disease later in life for both mother and baby. Notably, these women are at increased risk of hypertension, heart disease, and stroke, while offspring are at risk of obesity, hypertension, and neurological disease, among other complications, later in life. This article aims to discuss the current understanding of the diagnosis and pathophysiology of PE, as well as associated organ damage, maternal and fetal outcomes, and potential therapeutic avenues. © 2021 American Physiological Society. Compr Physiol 11:1315-1349, 2021.

The AT1 receptor autoantibody causes hypoglycemia in fetal rats via promoting the STT3A-GLUT1-glucose uptake axis in liver

Blood glucose is of great importance to development and metabolic homeostasis in fetuses. Stimulation of harmful factors during gestation induces pathoglycemia. Angiotensin II type 1 receptor autoantibody (AT1-AA), a newly discovered gestational harmful factor, has been shown to induce intrauterine growth restriction in fetuses and glucose disorders in adults. However, whether and how AT1-AA influences the blood glucose level of fetuses during gestation is not yet clear. The purpose of the current study was to observe the fetal blood glucose level of AT1-AA-positive pregnant rats during late pregnancy and to determine the roles that hepatic glucose transporters play in this process. We established AT1-AA-positive pregnant rats by injecting AT1-AA into the caudal veins of rats in the 2nd trimester of gestation. Although the fetal blood glucose level in the 3rd trimester of gestation decreased, hepatic glucose uptake increased detected. Through separating membrane and cytosolic proteins, we demonstrated that both the expression and membrane transport ratio of glucose transporter 1 (GLUT1), which is responsible for glucose transport in fetal hepatocytes, were upregulated, accompanied by increased expression of N-glycosyltransferase STT3A, which contributes to the N-glycosylation of GLUT1. In vitro, we identified that AT1-AA increased glucose uptake, the expression and membrane transport ratio of GLUT1 and the expression of STT3A in HepG2 cell lines via separating membrane and cytosolic proteins and immunofluorescence, resulting in the decreased glucose content in the medium. The GLUT1 inhibitor WZB117 reversed the decreases in glucose content in the medium, the increases in glucose uptake, the increases in the expression and membrane transport ratio of GLUT1 caused by AT1-AA. The N-glycosyltransferase inhibitor NGI as well as si-STT3A reversed the AT1-AA-induced upregulation of the STT3A-GLUT1-glucose uptake effect. This study demonstrates that AT1-AA lowers the blood glucose level of fetuses via the STT3A-GLUT1-glucose uptake axis in liver.

Increased AT2R expression is induced by AT1R autoantibody via two axes, Klf-5/IRF-1 and circErbB4/miR-29a-5p, to promote VSMC migration

Vascular remodeling can be caused by angiotensin II type 1 receptor (AT1R) autoantibody (AT1-AA), although the related mechanism remains unknown. Angiotensin II type 2 receptor (AT2R) plays multiple roles in vascular remodeling through cross-talk with AT1R in the cytoplasm. Here, we aimed to explore the role and mechanism of AT2R in AT1-AA-induced vascular smooth muscle cell (VSMC) migration, which is a key event in vascular remodeling. In vitro and in vivo, we found that AT2R can promote VSMC migration in AT1-AA-induced vascular remodeling. Moreover, AT2R expression was upregulated via Klf-5/IRF-1-mediated transcriptional and circErbB4/miR-29a-5p-mediated posttranscriptional mechanisms in response to AT1-AA. Our data provide a molecular basis for AT1-AA-induced AT2R expression by transcription factors, namely, a circular RNA and a microRNA, and showed that AT2R participated in AT1-AA-induced VSMC migration during the development of vascular remodeling. AT2R may be a potential target for the treatment of AT1-AA-induced vascular diseases.

Lipoxin A4 suppresses angiotensin II type 1 receptor autoantibody in preeclampsia via modulating caspase-1

Preeclampsia (PE) remains a leading cause of maternal and neonatal morbidity and mortality. Numerous studies have shown that women with PE develop autoantibody, termed angiotensin II type 1 receptor autoantibody (AT1-AA), and key features of the disease result from it. Emerging evidence has indicated that inflammatory cell necrosis, such as pyroptosis, could lead to autoantigen exposure and stimulate autoantibody production. Caspase-1, the central enzyme of inflammasome and key target of pyroptosis, may play roles in AT1R exposure and AT1-AA production. Exploring endogenous regulator that could inhibit AT1-AA production by targeting pyroptosis will be essential for treating PE. Lipoxin A4 (LXA4), endogenous dual anti-inflammatory and proresolving lipid mediator, may inhibit AT1-AA production via modulating caspase-1. Thus, we explore whether caspase-1 is essential for AT1-AA production and LXA4 inhibits AT1-AA via modulating caspase-1. PE patients and mice developed AT1-AA associated with caspase-1 activation. Caspase-1 deletion leaded to AT1-AA decrease in PE mice. Consistent with these findings, we confirmed caspase-1 activation, trophoblast pyroptosis and AT1R exposure in PE mice and trophoblast model, while caspase-1 deficiency showed decreased trophoblast pyroptosis and AT1R exposure in vitro and in vivo. Interestingly, LXA4 could suppress AT1-AA production via regulating caspase-1 as well as enhancing phagocytosis of dead trophoblasts by macrophages. These results suggest that caspase-1 promotes AT1-AA production via inducing trophoblast pyroptosis and AT1R exposure, while LXA4 suppresses AT1-AA production via modulating caspase-1, supporting caspase-1 serving as a therapeutic target for attenuating AT1-AA and LXA4 protecting patients from AT1-AA and PE.

Active immunization using hand-push emulsification method increases the operator's risk of transcutaneous immunization

Setting up an animal model by using active immunization methods is a common means of studying immune-related diseases or producing antibodies with high titer and high activities. However, the security during the process of pathogen emulsification remains unclear. In a physical examination, we unexpectedly noticed high levels of angiotensin II type 1 receptor autoantibody (AT1-AA) specific to the immunizing antigen in the sera of some researchers who had participated in setting up active immunization animal models, and we were puzzled about the cause of AT1-AA production. In this study, we intended to investigate whether the emulsified antigen was the source of infection in these researchers, and if so, how to prevent it from occurring.AT1-AA was detected by advanced ELISA method. The participants presented higher levels of AT1-AA compared with non-participants of the same laboratory. This phenomenon remained that some factors during the process of rat model establishment may contribute to AT1-AA production. Animal and glove penetration studies indicated the emulsified antigen infection was attributed to neither aerosol or fur touch nor penetrating through gloves. However, AT1-AA level was largely decreased in the participants after they used an automatic emulsification device. Because of the strong permeability of the adjuvant, we speculated that emulsified antigen might get access to the unprotected skin of the participants accidentally during the immunization process.These results demonstrated that accidental contacts of emulsified antigens may infect researchers during the process of traditional hand-push emulsification, resulting in high specific autoantibody levels, which can be prevented by using appropriate tools.

Abstract P252: Angiotensin II Type 1 Receptor Autoantibody Inhibited Bk Channels In Vascular Smooth Muscle Cells

Aims: The angiotensin II type 1 receptor autoantibody (AT1-AA) leads pathological sustainable vasoconstriction. Large-conductance Ca 2+ -and voltage-activated potassium (BK) channel, mainly consist by functional α subunits and modulatory β1 subunits in vascular smooth muscle cells (SMCs), plays a vital role on vascular relaxation. Recently, it has been found that AT1-AA inhibited BK channel’s function. However, the specific mechanisms remain unclear. In this study, we further investigated the open probability, Ca 2+ sensitivity and β1 subunits of BK channel after AT1-AA stimulation. Methods and Results: BKα subunit has several splicing variants. Immunofluorescence and PCR results showed that BK channels widely distributed among mesenteric artery (MA), most of them belong to zero-type. SMCs from MA were isolated freshly and used for patch clamp within 6 hours. AT1-AA downregulated the open probability of BK channel to 57.41±21.36% (the corresponding data of baseline was considered as 100%), specifically reduced the number of simultaneous opened channels (level 4 to level 2) instead of dwell time (T 1 =0.45 ms, T 2 = 3.39 ms to T 1 =0.58 ms, T 2 =4.99 ms) and amplitude (187.4 ±16.23 to 187.3 ±13.80 pS). This phenomenon could be reversed by BK channel agonist (NS1619) (enhanced to 124%). Noteworthy, different from Ang II, AT1-AA suppressed BK channel’s open probability consistently even after 15min (Ang II: recovered to 164.8%; AT1-AA, kept at 66.0%). The activated effect of Ca 2+ on BK channel nearly disappeared after bathing with AT1-AA in inside-out recording mode (vehicle: 100% to 471.6%; AT1-AA: 100% to 163.9%). Furthermore, to explore whether AT1-AA’s inhibitory effect on BK channel was independent from β1 subunit, only ZERO-BKα-GFP subunits were transfected into HEK293T cells. AT1-AA still diminished BK channels’ function to 57.35±5.4%. However, the inhibition of AT1-AA on BK channels was almost non-existent (to 92.1±12.81%) in AT1 receptor knock out rats. Conclusion: These results demonstrated that AT1-AA sustainably decreased open probability and Ca 2+ sensitivity of BK channels even if β1 subunit were absence. This effect was AT1 receptor dependent. It remains us that BK channel may become a novel target for improving AT1-AA related hypertension.

Abstract P257: Angiotensin Ii Type 1 Receptor Autoantibodies Decrease Angiotensin Ii Type 1 Receptor Internalization Through Attenuating The Recruitment Of β-arrestin1/2

Introduction: Angiotensin II type 1 receptor autoantibody (AT1-AA) can continuously activate angiotensin II type 1 receptor (AT 1 R), which is related to cardiovascular disease, but the exact mechanism remains obscure. The activated AT 1 R signaling is adjusted or terminated effectively via the internalization, which is mediated by β-arrestin1/2 dependent-endocytic pathways. The hypothesis is that AT1-AA can attenuate β-arrestin1/2 recruitment, leading to the decreased AT 1 R internalization and the sustained AT 1 R activation. Methods and Results: Firstly, subcellular protein fractionation and Total Internal Reflection Fluorescence were used to examine the AT 1 R internalization induced by AT1-AA. The results confirmed that AT1-AA limited the AT 1 R internalization. Then, by co-expressing YFP-labeled AT 1 R and RFP-labeled β-arrestin1/2 in HEK293 cells with different stimulant for 10 min, the image showed that AT 1 R and β-arrestin1/2 were co-localized in the cytoplasm with Ang II. However, there were rare co-localization with AT1-AA. To further investigate the AT1-AA-induced recruiting of β-arrestin1/2, we recorded the relative change of BRET ratio of the interaction between YFP-labeled AT 1 R with Rluc-labeled β-arrestin1/2. The relative change of BRET ratio was significantly elevated with the time [(the BRET ratio with Ang II for 10 min were considered as 100%; 0 (β-arrestin1/2: 0.33 ±0.58/0.00 ±1.46), 2 (89.10 ±19.36/69.27 ±4.47), 5 (107.08 ±12.17/89.27 ±1.46), 10 (100.22 ±0.38/100.00 ±13.12), 20 (93.45 ±11.59/102.93 ±10.38) and 30 min (101.45 ±16.93/114.15±8.15)] and with the concentration (EC50 β-arrestin1/2 =6.69 ±4.09/6.34 ±2.29 nmol/L) after Ang II treatment. However, AT1-AA could not induce the recruitment of β-arrestin1/2. Furthermore, pre-incubation with an inhibitor of β-arrestin1/2 dependent-endocytic pathways prolonged the duration of AT 1 R downstream PKC, ERK1/2 phosphorylation, elevate intracellular Ca 2+ and vasoconstriction caused by Ang II, which simulated AT1-AA-caused persistent AT 1 R activation. Conclusions: Our data suggested that reduced AT 1 R internalization caused by AT1-AA was attributed to the inhibition of β-arrestin1/2 recruitment, which played a key role in how AT1-AA prolonged receptor activation.

P161 Autoantibodies: Angiotensinogen vs AT1R as a target, Is there a correlation?

Aim Autoantibody directed at the Angiotensin II Type 1 Receptor (AT1R) has been reported as detrimental to solid organ transplants. An ELISA based AT1R antibody test is available, but presents challenges including different methodology, lot-to-lot variability, and cost effectiveness among them. A Luminex bead based assay autoantibody panel is available, currently detecting 33 targets, with more targets in development. One of the targets on the assay is Angiotensinogen (AGT), the precursor to Angiotensin II. This assay overcomes many of the challenges of the AT1R ELISA test. The aim of this study is to compare results of AGT autoantibody detection using the bead panel to the results of the AT1R autoantibody detection using the ELISA based testing. Methods OneLambda AT1R ELISA kits were used to test 30 sera from transplant patients for the presence of AT1R antibody. The trays were read on the VictorX and results were calculated using either the OneLambda 4PL curve calculation software, or the Workout Plus software on the VictorX, (validated as equivalent to the OneLambda software). OneLamda Autoantibody kits were used to test for the presence of antibody to angiotensinogen (AGT). The kit is a Luminex bead-based assay. Results were read on the Luminex 3D and results were analyzed using Fusion Research 6 software. Results The Reference values for the AGT target were determined by the manufacturer in a non-transplant population of 139 people. 75% had MFI of 777 or less, 85% had MFI of 1045 or less, and 95% had MFI of 1739 or less. Download : Download high-res image (578KB) Download : Download full-size image Conclusions These results show that ranges are overlapping and MFI mean values of AGN as a continuous variable are not consistent with the level of AT1R We conclude that there is no suggestion of a correlation between the results of both assays.

Hyperinsulinemia precedes insulin resistance in offspring rats exposed to angiotensin II type 1 autoantibody in utero.

Insulin resistance is highly associated with an adverse intrauterine environment. We previously reported that fetal rats exposed to angiotensin II type 1 receptor (AT1R) autoantibody (AT1-AA) displayed increased susceptibility to metabolic diseases during middle age. However, the timing of the onset of insulin resistance remains unknown. In this study, we examined the offspring of AT1-AA-positive rats, tracking the development of insulin resistance. Pregnant rats were intravenously injected with AT1-AA. Afterwards, we collected serum samples and liver tissues of the offspring at various stages, including gestation day 18, 3 weeks (weaning period), 18 weeks (young adulthood), and 48 weeks (middle age) after birth. Compared with saline control group, hepatic vacuolar degeneration was visible in AT1-AA offspring rats as early as 3 weeks; hyperinsulinemia and impaired glucose tolerance occurred at 18 weeks of age, however, insulin resistance was not observed until 48 weeks. At 18 weeks we detected suppressed protein levels of insulin receptor (IR) but increased levels of IR substrate 1 (IRS1) in the liver of AT1-AA group rats. Interestingly, both IR and IRS1/2 were significantly decreased at 48 weeks. Liver proteomic analysis indicated that the differences in protein expression between the AT1-AA and control rats became more pronounced with age, particularly in terms of mitochondrial energy metabolism. Rats exposed to AT1-AA in utero developed hyperinsulinemia from young adulthood which subsequently progressed to insulin resistance, and was linked with abnormal hepatic structure and impaired IR signaling. Additionally, dysregulation of energy metabolism may play a fundamental role in predisposing offspring to insulin resistance.

Long-term presence of angiotensin II type 1 receptor autoantibody reduces aldosterone production by triggering Ca2+ overload in H295R cells.

Preeclamptic women are reported to have inadequate plasma volume expansion coupled with a suppressed secretion of aldosterone; however, the specific mechanism of preeclampsia remains unclear. We demonstrated that the presence of long-term angiotensin II type 1 receptor autoantibody (AT1-AA) reduces aldosterone production by triggering a Ca2+ overload in H295R cells. AT1-AA was discovered in preeclamptic women and reported to activate AT1R, and consequently elevate intracellular Ca2+. We found that AT1-AA significantly prolonged the time of intracellular Ca2+ elevation. Besides promoting aldosterone production as a second messenger, Ca2+ overload shows a cytotoxic effect. Our data reveals that long-term presence of AT1-AA triggered a Ca2+ overload and consequent impairment of aldosterone production, which could be prevented by a PKC inhibitor, Gö 6983, or a calcium channel inhibitor, nifedipine. These findings have clinical significance because AT1R blockers are not recommended for treatment of preeclampsia due to their potential harm to the fetus. Our findings also emphasize a potential clinical benefit of immunoadsorption or neutralization of AT1-AA in preeclamptic women.

Effect of a black cumin (Nigella sativa) ethanol extract on placental angiotensin II type 1-receptor autoantibody (AT1-AA) serum levels and endothelin-1 (ET-1) expression in a preeclampsia mouse model.

ObjectivesPreeclampsia affects 3%–8% of all pregnancies. Thymoquinone is the primary compound in black cumin (Nigella sativa) and may have potential therapeutic effects in preeclampsia. This research analyses the effects of a black cumin seed ethanol extract on angiotensin II type 1-receptor autoantibody (AT1-AA) serum levels and the expression of the endothelin-1 (ET-1) in the placenta in preeclampsia mouse model.MethodsThe research design utilizes a post-test only experimental model on a control group design with 6 mice groups (negative control; positive control; and 500, 1000, 1500, and 2000 mg/kg body weight/day).ResultThe results showed a decrease in serum AT1-AA levels and ET-1 expression in the placenta by increased doses of black cumin with an optimal dose of 1000 mg/kg/day.ConclusionsBlack cumin seed ethanol extract reduces AT1-AA serum levels and represses ET-1 expression in the placenta in a preeclampsia mouse model.

The Endothelin Type A Receptor as a Potential Therapeutic Target in Preeclampsia.

Preeclampsia (PE) is a disorder of pregnancy typically characterized by new onset hypertension after gestational week 20 and proteinuria. Although PE is one of the leading causes of maternal and perinatal morbidity and death worldwide, the mechanisms of the pathogenesis of the disease remain unclear and treatment options are limited. However, there is increasing evidence to suggest that endothelin-1 (ET-1) plays a critical role in the pathophysiology of PE. Multiple studies report that ET-1 is increased in PE and some studies report a positive correlation between ET-1 and the severity of symptoms. A number of experimental models of PE are also associated with elevated tissue levels of prepro ET-1 mRNA. Moreover, experimental models of PE (placental ischemia, sFlt-1 infusion, Tumor necrosis factor (TNF) -α infusion, and Angiotensin II type 1 receptor autoantibody (AT1-AA) infusion) have proven to be susceptible to Endothelin Type A (ETA) receptor antagonism. While the results are promising, further work is needed to determine whether ET antagonists could provide an effective therapy for the management of preeclampsia.

The Prognostic Role of Angiotensin II Type 1 Receptor Autoantibody in Non-Gravid Hypertension and Pre-eclampsia: A Meta-analysis and Our Studies.

Angiotensin II type 1 receptor autoantibody (AT1-AA) is found in patients with non-gravid hypertension or pre-eclampsia, but the relationship is uncertain.The aim of the present study was to assess the association between AT1-AA and high blood pressure using meta-analysis, and to evaluate the prognosis value of AT1-AA for hypertensive diseases.Literature search from PubMed, Embase, and Cochrane databases were conducted using keywords "hypertension" or "pre-eclampsia," "angiotensin II receptor type 1 autoantibody," and its aliases from April 1999 to December 2015.Studies evaluating the association between AT1-AA and non-gravid hypertension or pre-eclampsia were included in this analysis. The quality of the eligible studies was assessed based on the Newcastle-Ottawa Scale with some modifications.Two researchers then independently reviewed all included studies and extracted all relevant data. Association between AT1-AA and hypertension was tested with pooled odds ratios (ORs) and 95% confidence intervals (CIs). Finally, we evaluated whether AT1-AA predicted the prognosis of hypertension by using a summary receiver-operating characteristic (ROC) curve and sensitivity analysis.Ten studies were finally included in this meta-analysis. AT1-AA showed more significant association with pre-eclampsia than that with non-gravid hypertension (pooled OR 32.84, 95% CI 17.19-62.74; and pooled OR 4.18, 95% CI 2.20-7.98, respectively). Heterogeneity among studies was also detected probably due to different hypertensive subtypes and AT1-AA measuring methods. Area under summary ROC curve (AUC) of pre-eclampsia was 0.92 (sensitivity 0.76; specificity 0.86). Area under the ROC curve of overall hypertensive diseases or non-gravid hypertension was lower than that of pre-eclampsia (0.86 and 0.72, respectively) with lower sensitivities (0.46 and 0.26, respectively).The major limitation of this analysis was the publication bias due to lack of unpublished data and the language limitation during literature search. Prospective study with large simple size and specific measuring data collection are needed to enhance our findings in the future.Our analysis confirms that elevated AT1-AA in serum is significantly associated with hypertensive disorder, especially pre-eclampsia. AT1-AA may be a valuable indicator for poorer prognosis of patients with pre-eclampsia, and could be used in patients with hypertensive disease for risk evaluation and making individual treatment decision.

Prevalence of angiotensin II type 1 receptor (AT1R)–activating autoantibodies in primary aldosteronism

Autoantibodies to the angiotensin II type 1 receptor (AT1R) have been reported in patients with primary aldosteronism, including aldosterone producing adenoma (APA) and idiopathic adrenal hyperplasia (IAH). Sera from 25 primary aldosteronism subjects (12 with IAH and 13 with APA) and 15 normotensive control subjects were assayed for AT1R autoantibodies by enzyme–linked immunosorbent assay and an AT1R–transfected cell–based bioassay. Nine of 12 IAH subjects (75%) and six of 13 APA subjects (46%) were positive for AT1R autoantibodies in the bioactivity assay. The mean AT1R autoantibody activity for the IAH and APA subjects was significantly greater than controls (P < .001 and P < .01, respectively), and this in vitro activity was suppressed by the AT1R blocker losartan. None of the controls had significant AT1R autoantibody activity. Enzyme–linked immunosorbent assay values were less sensitive but were positive in some subjects with IAH and APA. The mean arterial pressure of these primary aldosteronism subjects correlated modestly with AT1R autoantibody activity. These data confirm the presence of active AT1R autoantibodies in a high percentage of subjects with primary aldosteronism irrespective of their underlying etiology. These observations have both pathophysiological and clinical implications.

Physiology in Perspective: Addressing Cardiovascular Health and Disease

Basic research in cardiovascular physiology has provided essential answers for a wide spectrum of problems in cardiovascular disease and has led to evidence-based medicine. The cardiovascular system must properly function throughout life, and we owe it to ourselves to maintain this well designed

Recent Progress Toward the Understanding of the Pathophysiology of Hypertension During Preeclampsia

Studies published in Hypertension and other journals over the last few years have provided exciting new insights into potential mechanisms underlying the pathogenesis of hypertension during preeclampsia. Although numerous factors including genetic, immunologic, behavioral, and environmental influences have been implicated in the pathogenesis of preeclampsia, the main focus of this Hypertension Highlight is to review recent studies that link endothelial dysfunction and hypertension in preeclampsia.1–11 The pathophysiologic processes that underlie preeclampsia has been proposed to occur in 2 stages: stage 1, reduced placental perfusion, and stage 2, the maternal clinical syndrome.1,4 Placental ischemia/hypoxia is believed to result in the release of a variety of placental factors that have profound effects on blood flow and arterial pressure regulation.1,4,10,11 These factors include a host of molecules such as the soluble VEGF receptor-1 (sFlt-1), the angiotensin II type-1 receptor autoantibody (AT1-AA), and cytokines such as tumor necrosis factor (TNF)-α which in turn generate widespread dysfunction of the maternal vascular endothelium.1–11 This dysfunction manifests as enhanced formation of factors such as endothelin, reactive oxygen species (ROS), thromboxane, 20-HETE, and augmented vascular sensitivity to angiotensin II.1–11 In addition, preeclampsia is also associated with decreased formation of vasodilators such as nitric oxide (NO) and prostacyclin.1–11 These alterations in vascular function not only lead to hypertension but multi-organ dysfunction, especially in women with early onset preeclampsia.1,4,11–20 Preterm preeclampsia remains a leading cause of maternal death and perinatal morbidity. Moreover, it has recently been recognized that women who endure preeclampsia are at a greater risk for cardiovascular disease later in life. Therefore, identifying the connection between placental ischemia/hypoxia and maternal cardiovascular abnormalities is an important area of investigation.1,10,11,21 In addition, the quantitative importance of the various endothelial and humoral factors that mediate vascular dysfunction and hypertension during preeclampsia remains to …