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

Ranjit, Sanjay; Wong, Jian Yao; Tan, Jia Wei; Tay, Chee Sin; Lee, Jessica M.; Wong, Kelly Yin Han; Pojoga, Luminita H.; Garza, Amanda E; Maris, Stephen; Katayama, Isis Akemi; Williams, Jonathan S.; Rivera, Alicia; Adler, Gail K.; Williams, Gordon H.; Romero, José R.

doi:10.1172/jci.insight.129615

Cited by 13 publications

(15 citation statements)

References 48 publications

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“…Furthermore, ERAPs modulate the proteolytic cleavage of IL-6 receptor (IL-6Rα) [ 40 ] a function which can improve the clinical conditions in COVID-19 patients, as recently documented following its pharmacological inhibition by Tocilizumab [ 41 ]. Last but not least, Ranjit and colleagues recently demonstrated that sex-specific differences in ERAP1 modulation influence blood pressure and RAS responses [ 42 ], and a male bias in mortality has emerged in the COVID-19 pandemic since the very beginning. As ERAPs genetic variants have been demonstrated to orchestrate and condition the result of infection of coronavirus in other animal species [ 43 , 44 ] detailed studies investigating SARS-CoV-2-host interplay is absolutely mandatory.…”

Section: Discussionmentioning

confidence: 99%

A New ERAP2/Iso3 Isoform Expression Is Triggered by Different Microbial Stimuli in Human Cells. Could It Play a Role in the Modulation of SARS-CoV-2 Infection?

Saulle

Vanetti

Goglia

et al. 2020

Cells

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Following influenza infection, rs2248374-G ERAP2 expressing cells may transcribe an alternative spliced isoform: ERAP2/Iso3. This variant, unlike ERAP2-wt, is unable to trim peptides to be loaded on MHC class I molecules, but it can still dimerize with both ERAP2-wt and ERAP1-wt, thus contributing to profiling an alternative cellular immune-peptidome. In order to verify if the expression of ERAP2/Iso3 may be induced by other pathogens, PBMCs and MDMs isolated from 20 healthy subjects were stimulated with flu, LPS, CMV, HIV-AT-2, SARS-CoV-2 antigens to analyze its mRNA and protein expression. In parallel, Calu3 cell lines and PBMCs were in vitro infected with growing doses of SARS-CoV-2 (0.5, 5, 1000 MOI) and HIV-1BAL (0.1, 1, and 10 ng p24 HIV-1Bal/1 × 106 PBMCs) viruses, respectively. Results showed that: (1) ERAP2/Iso3 mRNA expression can be prompted by many pathogens and it is coupled with the modulation of several determinants (cytokines, interferon-stimulated genes, activation/inhibition markers, antigen-presentation elements) orchestrating the anti-microbial immune response (Quantigene); (2) ERAP2/Iso3 mRNA is translated into a protein (western blot); (3) ERAP2/Iso3 mRNA expression is sensitive to SARS-CoV-2 and HIV-1 concentration. Considering the key role played by ERAPs in antigen processing and presentation, it is conceivable that these enzymes may be potential targets and modulators of the pathogenicity of infectious diseases and further analyses are needed to define the role played by the different isoforms.

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Section: Discussionmentioning

confidence: 99%

A New ERAP2/Iso3 Isoform Expression Is Triggered by Different Microbial Stimuli in Human Cells. Could It Play a Role in the Modulation of SARS-CoV-2 Infection?

Saulle

Vanetti

Goglia

et al. 2020

Cells

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“…However, the secretion of these molecules apparently occurs in activated macrophages and might have different outcomes: i.e., the triggering of a vascular response relevant in the inflammatory process accompanying these diseases. In humans for example, ERAP1 rs30187, a loss-of function gene variant that reduces AngII degradation in vitro , is associated with hypertension ( 54 ). The role of LNPEP in the RAS is well-documented as well as the association of ERAP2 with preeclampsia.…”

Section: Do the Three Aminopeptidases Have An Extracellular Role?mentioning

confidence: 99%

The Multifaceted Nature of Aminopeptidases ERAP1, ERAP2, and LNPEP: From Evolution to Disease

et al. 2020

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In the human genome, the aminopeptidases ERAP1, ERAP2 and LNPEP lie contiguously on chromosome 5. They share sequence homology, functions and associations with immune-mediated diseases. By analyzing their multifaceted activities as well as their expression in the zoological scale, we suggest here that the progenitor of the three aminopeptidases might be LNPEP from which the other two aminopeptidases could have derived by gene duplications. We also propose that their functions are partially redundant. More precisely, the evolutionary story of the three aminopeptidases might have been dictated by their role in regulating the renin–angiotensin system, which requires their controlled and coordinated expression. This hypothesis is supported by the many species that lack one or the other gene as well as by the lack of ERAP2 in rodents and a null expression in 25% of humans. Finally, we speculate that their role in antigen presentation has been acquired later on during evolution. They have therefore been diversified between those residing in the ER, ERAP1 and ERAP2, whose role is to refine the MHC-I peptidomes, and LNPEP, mostly present in the endosomal vesicles where it can contribute to antigen cross-presentation or move to the cell membrane as receptor for angiotensin IV. Their association with autoinflammatory/autoimmune diseases can therefore be two-fold: as “contributors” to the shaping of the immune-peptidomes as well as to the regulation of the vascular response.

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“…Dysfunctional genetic variants have been linked to the onset of autoimmune disease and viral infections [ 33 , 34 , 35 , 36 , 37 ]. Interestingly, most of these variants are also associated with essential hypertension and treatment responses in patients with left ventricular hypertrophy [ 38 , 39 , 40 , 41 , 42 , 43 ], further supporting their role in regulating blood pressure and cardiac remodeling ( Table 1 ).…”

Section: Erap1 and Erap2 Genmentioning

confidence: 86%

“…Dysfunctional genetic variants have been linked to the onset of autoimmune disease and viral infections [33][34][35][36][37]. Interestingly, most of these variants are also associated with essential hypertension and treatment responses in patients with left ventricular hypertrophy [38][39][40][41][42][43], further supporting their role in regulating blood pressure and cardiac remodeling ( Table 1). Zee and colleagues evaluated the potential association of 33 ERAP1 and 12 ERAP2 single nucleotide polymorphisms (SNPs) with blood pressure progression and incident hypertension in a cohort of 17,255 initially healthy White U.S. women (Table 1) [39].…”

Section: Erap1 and Erap2 Gene Polymorphisms Associated With Hypertensionmentioning

confidence: 93%

“…Moreover, the ERAP1 rs30187 loss of function variant (K528R) was linked to the reduced degradation of Ang II and essential hypertension in a cohort of 143 hypertensive and 348 normotensive Japanese subjects ( Table 1 ) [ 41 , 42 ]. Ranjit and colleagues showed a significant association between the ERAP1 rs30187 variant, volume expansion, and increased systolic and diastolic blood pressure in a cohort of 435 patients involved in the Hypertensive Pathotype (HyperPATH) Consortium, with stronger evidence in males [ 43 ]. Nevertheless, men bearing the rs30187 allele displayed elevated aldosterone (ALDO) levels with normal renovascular function as compared to women [ 43 ].…”

Section: Erap1 and Erap2 Genmentioning

confidence: 99%

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ERAP1 and ERAP2 Enzymes: A Protective Shield for RAS against COVID-19?

D’Amico

Tempora

Lucarini

et al. 2021

IJMS

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Patients with coronavirus disease 2019 (COVID-19) have a wide variety of clinical outcomes ranging from asymptomatic to severe respiratory syndrome that can progress to life-threatening lung lesions. The identification of prognostic factors can help to improve the risk stratification of patients by promptly defining for each the most effective therapy to resolve the disease. The etiological agent causing COVID-19 is a new coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that enters cells via the ACE2 receptor. SARS-CoV-2 infection causes a reduction in ACE2 levels, leading to an imbalance in the renin–angiotensin system (RAS), and consequently, in blood pressure and systemic vascular resistance. ERAP1 and ERAP2 are two RAS regulators and key components of MHC class I antigen processing. Their polymorphisms have been associated with autoimmune and inflammatory conditions, hypertension, and cancer. Based on their involvement in the RAS, we believe that the dysfunctional status of ERAP1 and ERAP2 enzymes may exacerbate the effect of SARS-CoV-2 infection, aggravating the symptomatology and clinical outcome of the disease. In this review, we discuss this hypothesis.

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

Cited by 13 publications

References 48 publications

A New ERAP2/Iso3 Isoform Expression Is Triggered by Different Microbial Stimuli in Human Cells. Could It Play a Role in the Modulation of SARS-CoV-2 Infection?

A New ERAP2/Iso3 Isoform Expression Is Triggered by Different Microbial Stimuli in Human Cells. Could It Play a Role in the Modulation of SARS-CoV-2 Infection?

The Multifaceted Nature of Aminopeptidases ERAP1, ERAP2, and LNPEP: From Evolution to Disease

ERAP1 and ERAP2 Enzymes: A Protective Shield for RAS against COVID-19?

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