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      Sex-specific differences in endoplasmic reticulum aminopeptidase 1 modulation influence blood pressure and renin-angiotensin system responses

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          Abstract

          Salt sensitivity of blood pressure (SSBP) and hypertension are common, but the underlying mechanisms remain unclear. Endoplasmic reticulum aminopeptidase 1 (ERAP1) degrades angiotensin II (ANGII). We hypothesized that decreasing ERAP1 increases BP via ANGII-mediated effects on aldosterone (ALDO) production and/or renovascular function. Compared with WT littermate mice, ERAP1-deficient (ERAP1 +/– ) mice had increased tissue ANGII, systolic and diastolic BP, and SSBP, indicating that ERAP1 deficiency leads to volume expansion. However, the mechanisms underlying the volume expansion differed according to sex. Male ERAP1 +/– mice had increased ALDO levels and normal renovascular responses to volume expansion (decreased resistive and pulsatility indices and increased glomerular volume). In contrast, female ERAP1 +/– mice had normal ALDO levels but lacked normal renovascular responses. In humans, ERAP1 rs30187, a loss-of-function gene variant that reduces ANGII degradation in vitro, is associated with hypertension. In our cohort from the Hypertensive Pathotype (HyperPATH) Consortium, there was a significant dose-response association between rs30187 risk alleles and systolic and diastolic BP as well as renal plasma flow in men, but not in women. Thus, lowering ERAP1 led to volume expansion and increased BP. In males, the volume expansion was due to elevated ALDO with normal renovascular function, whereas in females the volume expansion was due to impaired renovascular function with normal ALDO levels. Reducing ERAP1 increased blood pressure due to elevated aldosterone in male mice, whereas female mice showed impaired renovascular function.

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          Most cited references40

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          The Genotype-Tissue Expression (GTEx) Project.

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            Concerted peptide trimming by human ERAP1 and ERAP2 aminopeptidase complexes in the endoplasmic reticulum.

            The generation of many HLA class I peptides entails a final trimming step in the endoplasmic reticulum that, in humans, is accomplished by two 'candidate' aminopeptidases. We show here that one of these, ERAP1, was unable to remove several N-terminal amino acids that were trimmed efficiently by the second enzyme, ERAP2. This trimming of a longer peptide required the concerted action of both ERAP1 and ERAP2, both for in vitro digestion and in vivo for cellular antigen presentation. ERAP1 and ERAP2 localized together in vivo and associated physically in complexes that were most likely heterodimeric. Thus, the human endoplasmic reticulum is equipped with a pair of trimming aminopeptidases that have complementary functions in HLA class I peptide presentation.
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              Do men and women respond differently to blood pressure-lowering treatment? Results of prospectively designed overviews of randomized trials.

              Large-scale observational studies show that lower blood pressure is associated with lower cardiovascular risk in both men and women although some studies have suggested that different outcomes between the sexes may reflect different responses to blood pressure-lowering treatment. The aims of these overview analyses were to quantify the effects of blood pressure-lowering treatment in each sex and to determine if there are important differences in the proportional benefits of treatment between men and women. Thirty-one randomized trials that included 103,268 men and 87,349 women contributed to these analyses. For each outcome and each comparison summary estimates of effect and 95% confidence intervals were calculated for men and women using a random-effects model. The consistency of the effects of each treatment regimen across the sexes was examined using chi(2) tests of homogeneity. Achieved blood pressure reductions were comparable for men and women in every comparison made. For the primary outcome of total major cardiovascular events there was no evidence that men and women obtained different levels of protection from blood pressure lowering or that regimens based on angiotensin-converting-enzyme inhibitors, calcium antagonists, angiotensin receptor blockers, or diuretics/beta-blockers were more effective in one sex than the other (all P-homogeneity > 0.08). All of the blood pressure-lowering regimens studied here provided broadly similar protection against major cardiovascular events in men and women. Differences in cardiovascular risks between sexes are unlikely to reflect differences in response to blood pressure-lowering treatments.
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                Author and article information

                Journal
                JCI Insight
                American Society for Clinical Investigation
                2379-3708
                November 1 2019
                November 1 2019
                November 1 2019
                November 1 2019
                : 4
                : 21
                Article
                10.1172/jci.insight.129615
                6948756
                31672933
                394a6673-377a-42d0-ae15-05580988a6a1
                © 2019
                History

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