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Immunity Aug 2023Lung infection during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) via the angiotensin-I-converting enzyme 2 (ACE2) receptor induces a cytokine storm....
Lung infection during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) via the angiotensin-I-converting enzyme 2 (ACE2) receptor induces a cytokine storm. However, the precise mechanisms involved in severe COVID-19 pneumonia are unknown. Here, we showed that interleukin-10 (IL-10) induced the expression of ACE2 in normal alveolar macrophages, causing them to become vectors for SARS-CoV-2. The inhibition of this system in hamster models attenuated SARS-CoV-2 pathogenicity. Genome-wide association and quantitative trait locus analyses identified a IFNAR2-IL10RB readthrough transcript, COVID-19 infectivity-enhancing dual receptor (CiDRE), which was highly expressed in patients harboring COVID-19 risk variants at the IFNAR2 locus. We showed that CiDRE exerted synergistic effects via the IL-10-ACE2 axis in alveolar macrophages and functioned as a decoy receptor for type I interferons. Collectively, our data show that high IL-10 and CiDRE expression are potential risk factors for severe COVID-19. Thus, IL-10R and CiDRE inhibitors might be useful COVID-19 therapies.
Topics: Humans; COVID-19; SARS-CoV-2; Angiotensin-Converting Enzyme 2; Interleukin-10; Macrophages, Alveolar; Genome-Wide Association Study; Peptidyl-Dipeptidase A
PubMed: 37442134
DOI: 10.1016/j.immuni.2023.06.013 -
Blood Pressure Dec 2023We investigated plasma angiotensin-converting enzyme 2 (ACE2) concentration in a population sample and the ACE2 expression quantitated with the diaminobenzidine mean...
PURPOSE
We investigated plasma angiotensin-converting enzyme 2 (ACE2) concentration in a population sample and the ACE2 expression quantitated with the diaminobenzidine mean intensity in the lung tissue in patients who underwent lung surgery.
MATERIALS AND METHODS
The study participants were recruited from a residential area in the suburb of Shanghai for the plasma ACE2 concentration study ( = 503) and the lung tissue samples were randomly selected from the storage in Ruijin Hospital (80 men and 78 age-matched women).
RESULTS
In analyses adjusted for covariables, men had a significantly higher plasma ACE2 concentration (1.21 . 0.98 ng/mL, = 0.027) and the mean intensity of ACE2 in the lung tissue (55.1 . 53.9 a.u., = 0.037) than women. With age increasing, plasma ACE2 concentration decreased ( = 0.001), while the mean intensity of ACE2 in the lung tissue tended to increase ( = 0.087). Plasma ACE2 concentration was higher in hypertension than normotension, especially treated hypertension (1.23 . 0.98 ng/mL, = 0.029 . normotension), with no significant difference between users of RAS inhibitors and other classes of antihypertensive drugs ( = 0.64). There was no significance of the mean intensity of ACE2 in the lung tissue between patients taking and those not taking RAS inhibitors ( = 0.14). Neither plasma ACE2 concentration nor the mean intensity of ACE2 in the lung tissue differed between normoglycemia and diabetes ( ≥ 0.20).
CONCLUSION
ACE2 in the plasma and lung tissue showed divergent changes according to several major characteristics of patients.Plain language summary • The primary physiological function of ACE2 is the degradation of angiotensin I and II to angiotensin 1-9 and 1-7, respectively. • ACE2 was found to behave as a mediator of the severe acute respiratory syndrome coronavirus (SARS) infection. • There is little research on ACE2 in humans, especially in the lung tissue. • In the present report, we investigated plasma ACE2 concentration and the ACE2 expression quantitated with the diaminobenzidine mean intensity in the lung tissue respectively in two study populations. • Our study investigated both circulating and tissue ACE2 in human subjects. The main findings were: • In men as well as women, plasma ACE2 concentration was higher in younger than older participants, whereas the mean intensity of ACE2 in the lung tissue increase with age increasing. • Compared with normotension, hypertensive patients had higher plasma ACE2 concentration but similar mean intensity of ACE2 in the lung tissue. • Neither plasma ACE2 concentration nor lung tissue ACE2 expression significantly differed between users of RAS inhibitors and other classes of antihypertensive drugs. • ACE2 in the plasma and lung tissue showed divergent changes according to several major characteristics, such as sex, age, and treated and untreated hypertension. • A major implication is that plasma ACE2 concentration might not be an appropriate surrogate for the ACE2 expression in the lung tissue, and hence not a good predictor of SARS-COV-2 infection or fatality.
Topics: Male; Humans; Female; Angiotensin-Converting Enzyme 2; COVID-19; SARS-CoV-2; Peptidyl-Dipeptidase A; Antihypertensive Agents; Renin-Angiotensin System; China; Angiotensin I; Hypertension; Lung
PubMed: 36495008
DOI: 10.1080/08037051.2022.2154745 -
World Journal of Diabetes Apr 2024Coronavirus disease 2019 (COVID-19) is a disease that caused a global pandemic and is caused by infection of severe acute respiratory syndrome coronavirus 2 virus. It... (Review)
Review
Coronavirus disease 2019 (COVID-19) is a disease that caused a global pandemic and is caused by infection of severe acute respiratory syndrome coronavirus 2 virus. It has affected over 768 million people worldwide, resulting in approximately 6900000 deaths. High-risk groups, identified by the Centers for Disease Control and Prevention, include individuals with conditions like type 2 diabetes mellitus (T2DM), obesity, chronic lung disease, serious heart conditions, and chronic kidney disease. Research indicates that those with T2DM face a heightened susceptibility to COVID-19 and increased mortality compared to non-diabetic individuals. Examining the renin-angiotensin system (RAS), a vital regulator of blood pressure and pulmonary stability, reveals the significance of the angiotensin-converting enzyme (ACE) and ACE2 enzymes. ACE converts angiotensin-I to the vasoconstrictor angiotensin-II, while ACE2 counters this by converting angiotensin-II to angiotensin 1-7, a vasodilator. Reduced ACE2 expression, common in diabetes, intensifies RAS activity, contributing to conditions like inflammation and fibrosis. Although ACE inhibitors and angiotensin receptor blockers can be therapeutically beneficial by increasing ACE2 levels, concerns arise regarding the potential elevation of ACE2 receptors on cell membranes, potentially facilitating COVID-19 entry. This review explored the role of the RAS/ACE2 mechanism in amplifying severe acute respiratory syndrome coronavirus 2 infection and associated complications in T2DM. Potential treatment strategies, including recombinant human ACE2 therapy, broad-spectrum antiviral drugs, and epigenetic signature detection, are discussed as promising avenues in the battle against this pandemic.
PubMed: 38680697
DOI: 10.4239/wjd.v15.i4.606 -
Physiological Research Mar 2024Angiotensin-converting enzyme 2 (ACE2), one of the key enzymes of the renin-angiotensin system (RAS), plays an important role in SARS-CoV-2 infection by functioning as a...
Angiotensin-converting enzyme 2 (ACE2), one of the key enzymes of the renin-angiotensin system (RAS), plays an important role in SARS-CoV-2 infection by functioning as a virus receptor. Angiotensin peptides Ang I and Ang II, the substrates of ACE2, can modulate the binding of SARS-CoV-2 Spike protein to the ACE2 receptor. In the present work, we found that co incubation of HEK-ACE2 and Vero E6 cells with the SARS-CoV-2 Spike pseudovirus (PVP) resulted in stimulation of the virus entry at low and high micromolar concentrations of Ang I and Ang II, respectively. The potency of Ang I and Ang II stimulation of virus entry corresponds to their binding affinity to ACE2 catalytic pocket with 10 times higher efficiency of Ang II. The Ang II induced mild increase of PVP infectivity at 20 microM; while at 100 microM the increase (129.74+/-3.99 %) was highly significant (p<0.001). Since the angiotensin peptides act in HEK ACE2 cells without the involvement of angiotensin type I receptors, we hypothesize that there is a steric interaction between the catalytic pocket of the ACE2 enzyme and the SARS-CoV-2 S1 binding domain. Oversaturation of the ACE2 with their angiotensin substrate might result in increased binding and entry of the SARS-CoV-2. In addition, the analysis of angiotensin peptides metabolism showed decreased ACE2 and increased ACE activity upon SARS-CoV-2 action. These effects should be taken into consideration in COVID-19 patients suffering from comorbidities such as the over-activated renin-angiotensin system as a mechanism potentially influencing the SARS-CoV-2 invasion into recipient cells.
Topics: Humans; Renin-Angiotensin System; SARS-CoV-2; Angiotensin-Converting Enzyme 2; COVID-19; Angiotensin I; Peptidyl-Dipeptidase A; Angiotensin-Converting Enzyme Inhibitors; Angiotensin II; Spike Glycoprotein, Coronavirus
PubMed: 38466002
DOI: 10.33549/physiolres.935198 -
Biochemical Pharmacology Feb 2024Normal pregnancy (Norm-Preg) is associated with a slight reduction in blood pressure (BP) and decreased BP response to vasoconstrictor stimuli such as angiotensin II... (Review)
Review
Normal pregnancy (Norm-Preg) is associated with a slight reduction in blood pressure (BP) and decreased BP response to vasoconstrictor stimuli such as angiotensin II (Ang II), although the renin-angiotensin-aldosterone system (RAAS) is upregulated. Preeclampsia (PE) is a complication of pregnancy manifested as hypertension-in-pregnancy (HTN-Preg), and dysregulation of angiotensin biosynthesis and signaling have been implicated. Ang II activates vascular Ang II type-1 receptor (ATR) and Ang II type-2 receptor (ATR), while angiotensin-(1-7) promotes Ang-(1-7)/MasR signaling. The role of ATR in vasoconstriction and the activated cellular mechanisms are well-characterized. The sensitivity of vascular ATR to Ang II and consequent activation of vasoconstrictor mechanisms decrease during Norm-Preg, but dramatically increase in HTN-Preg. Placental ischemia in late pregnancy could also initiate the release of ATR agonistic autoantibodies (ATAA) with significant impact on endothelial dysfunction and activation of contraction pathways in vascular smooth muscle including [Ca] and protein kinase C. On the other hand, the role of ATR and Ang-(1-7)/MasR in vascular relaxation, particularly during Norm-Preg and PE, is less clear. During Norm-Preg, increases in the expression/activity of vascular ATR and Ang-(1-7)/MasR promote the production of endothelium-derived relaxing factors such as nitric oxide (NO), prostacyclin and endothelium-derived hyperpolarizing factor leading to generalized vasodilation. Aortic segments of Preg rats show prominent endothelial ATR staining and increased relaxation and NO production in response to ATR agonist CGP42112A, and treatment with ATR antagonist PD123319 enhances phenylephrine-induced contraction. Decreased vascular ATR and Ang-(1-7)/MasR expression and receptor-mediated mechanisms of vascular relaxation have been suggested in HTN-Preg animal models, but their role in human PE needs further testing. Changes in angiotensin-converting enzyme-2 (ACE2) have been observed in COVID-19 patients, and whether ACE2 influences the course of COVID-19 viral infection/immunity in Norm-Preg and PE is an intriguing area for research.
Topics: Animals; Female; Humans; Pregnancy; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; Biological Factors; COVID-19; Hypertension; Peptide Fragments; Placenta; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Vasoconstrictor Agents
PubMed: 38061417
DOI: 10.1016/j.bcp.2023.115963 -
Kidney International Aug 2023Chronic kidney disease is one of the leading causes of morbidity and mortality especially among the aged population. A decline in kidney function with ageing comparable...
Chronic kidney disease is one of the leading causes of morbidity and mortality especially among the aged population. A decline in kidney function with ageing comparable to ageing-related processes in human kidneys has also been described in Sprague-Dawley (SD) rats. The renin-angiotensin-system (RAS) plays a pivotal role in the pathophysiology of cardiovascular and kidney disease and is a successful therapeutic target. The discovery of angiotensin-(1-7) (Ang(1-7)), mainly produced by angiotensin-converting enzyme 2 (ACE2), and its receptor MAS offered a new view on the RAS. This ACE2/Ang(1-7)/MAS axis counteracts most deleterious actions of the RAS in the kidney. In order to evaluate if activation of this axis has a protective effect in ageing-induced kidney disease we generated a transgenic rat model (TGR(SM22hACE2)) overexpressing human ACE2 in vascular smooth muscle cells. These animals showed a specific transgene expression pattern and increased ACE2 activity in the kidney. Telemetric recording of cardiovascular parameters and evaluation of kidney function by histology and urine analysis revealed no alterations in blood pressure regulation and basal kidney function in young transgenic rats when compared to young SD rats. However, with ageing, SD rats developed a decline in kidney function characterized by severe albuminuria which was significantly less pronounced in TGR(SM22hACE2) rats. Concomitantly, we detected lower mRNA expression levels of kidney damage markers in aged transgenic animals. Thus, our results indicate that vascular ACE2-overexpression protects the kidney against ageing-induced decline in kidney function, supporting the kidney-protective role of the ACE2/Ang(1-7)/MAS axis.
Topics: Rats; Animals; Humans; Aged; Peptidyl-Dipeptidase A; Angiotensin-Converting Enzyme 2; Rats, Sprague-Dawley; Renin-Angiotensin System; Kidney; Peptide Fragments; Rats, Transgenic; Renal Insufficiency, Chronic; Aging; Angiotensin I; Receptors, G-Protein-Coupled
PubMed: 37105519
DOI: 10.1016/j.kint.2023.04.007 -
World Journal of Gastroenterology May 2024This editorial contains comments on the article by Zhao in print in the . The mechanisms responsible for hepatic fibrosis are also involved in cancerogenesis. Here, we...
This editorial contains comments on the article by Zhao in print in the . The mechanisms responsible for hepatic fibrosis are also involved in cancerogenesis. Here, we recapitulated the complexity of the renin-angiotensin system, discussed the role of hepatic stellate cell (HSC) autophagy in liver fibrogenesis, and analyzed the possible implications in the development of hepatocarcinoma (HCC). Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers definitively contribute to reducing hepatic fibrogenesis, whereas their involvement in HCC is more evident in experimental conditions than in human studies. Angiotensin-converting enzyme 2 (ACE2), and its product Angiotensin (Ang) 1-7, not only regulate HSC autophagy and liver fibrosis, but they also represent potential targets for unexplored applications in the field of HCC. Finally, ACE2 overexpression inhibits HSC autophagy through the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway. In this case, Ang 1-7 acts binding to the MasR, and its agonists could modulate this pathway. However, since AMPK utilizes different targets to suppress the mTOR downstream complex mTOR complex 1 effectively, we still need to unravel the entire pathway to identify other potential targets for the therapy of fibrosis and liver cancer.
Topics: Humans; TOR Serine-Threonine Kinases; Angiotensin-Converting Enzyme 2; Liver Cirrhosis; AMP-Activated Protein Kinases; Signal Transduction; Autophagy; Hepatic Stellate Cells; Liver Neoplasms; Carcinoma, Hepatocellular; Renin-Angiotensin System; Angiotensin I; Animals; Peptidyl-Dipeptidase A; Angiotensin-Converting Enzyme Inhibitors; Peptide Fragments; Angiotensin Receptor Antagonists; Liver
PubMed: 38764773
DOI: 10.3748/wjg.v30.i18.2391 -
Effects of Angiotensin 1-7 and Mas Receptor Agonist on Renal System in a Rat Model of Heart Failure.International Journal of Molecular... Jul 2023Congestive heart failure (CHF) is often associated with impaired kidney function. Over- activation of the renin-angiotensin-aldosterone system (RAAS) contributes to avid...
Congestive heart failure (CHF) is often associated with impaired kidney function. Over- activation of the renin-angiotensin-aldosterone system (RAAS) contributes to avid salt/water retention and cardiac hypertrophy in CHF. While the deleterious effects of angiotensin II (Ang II) in CHF are well established, the biological actions of angiotensin 1-7 (Ang 1-7) are not fully characterized. In this study, we assessed the acute effects of Ang 1-7 (0.3, 3, 30 and 300 ng/kg/min, IV) on urinary flow (UF), urinary Na excretion (UNaV), glomerular filtration rate (GFR) and renal plasma flow )RPF) in rats with CHF induced by the placement of aortocaval fistula. Additionally, the chronic effects of Ang 1-7 (24 µg/kg/h, via intra-peritoneally implanted osmotic minipumps) on kidney function, cardiac hypertrophy and neurohormonal status were studied. Acute infusion of either Ang 1-7 or its agonist, AVE 0991, into sham controls, but not CHF rats, increased UF, UNaV, GFR, RPF and urinary cGMP. In the chronic protocols, untreated CHF rats displayed lower cumulative UF and UNaV than their sham controls. Chronic administration of Ang 1-7 and AVE 0991 exerted significant diuretic, natriuretic and kaliuretic effects in CHF rats, but not in sham controls. Serum creatinine and aldosterone levels were significantly higher in vehicle-treated CHF rats as compared with controls. Treatment with Ang 1-7 and AVE 0991 reduced these parameters to comparable levels observed in sham controls. Notably, chronic administration of Ang 1-7 to CHF rats reduced cardiac hypertrophy. In conclusion, Ang 1-7 exerts beneficial renal and cardiac effects in rats with CHF. Thus, we postulate that ACE2/Ang 1-7 axis represents a compensatory response to over-activity of ACE/AngII/AT1R system characterizing CHF and suggest that Ang 1-7 may be a potential therapeutic agent in this disease state.
Topics: Rats; Animals; Heart Failure; Kidney; Angiotensin I; Peptide Fragments; Cardiomegaly; Renin-Angiotensin System; Angiotensin II
PubMed: 37511227
DOI: 10.3390/ijms241411470 -
Marine Drugs Sep 2023The objective of this study was to isolate and characterize collagen and angiotensin-I-converting enzyme (ACE)-inhibitory (ACEi) peptides from the swim bladders of...
Angiotensin-I-Converting Enzyme (ACE)-Inhibitory Peptides from the Collagens of Monkfish () Swim Bladders: Isolation, Characterization, Molecular Docking Analysis and Activity Evaluation.
The objective of this study was to isolate and characterize collagen and angiotensin-I-converting enzyme (ACE)-inhibitory (ACEi) peptides from the swim bladders of monkfish (). Therefore, acid-soluble collagen (ASC-M) and pepsin-soluble collagen (PSC-M) with yields of 4.27 ± 0.22% and 9.54 ± 0.51%, respectively, were extracted from monkfish swim bladders using acid and enzyme methods. The ASC-M and PSC-M contained Gly (325.2 and 314.9 residues/1000 residues, respectively) as the major amino acid, but they had low imino acid content (192.5 and 188.6 residues/1000 residues, respectively) in comparison with collagen from calf skins (CSC) (216.6 residues/1000 residues). The sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) patterns and ultraviolet (UV) absorption spectrums of ASC-M and PSC-M illustrated that they were mainly composed of type I collagen. Subsequently, three ACEi peptides were isolated from a PSC-M hydrolysate prepared via a double-enzyme system (alcalase + neutrase) and identified as SEGPK (MHP6), FDGPY (MHP7) and SPGPW (MHP9), with molecular weights of 516.5, 597.6 and 542.6 Da, respectively. SEGPK, FDGPY and SPGPW displayed remarkable anti-ACE activity, with IC values of 0.63, 0.94 and 0.71 mg/mL, respectively. Additionally, a molecular docking assay demonstrated that the affinities of SEGPK, FDGPY and SPGPW with ACE were -7.3, -10.9 and -9.4 kcal/mol, respectively. The remarkable ACEi activity of SEGPK, FDGPY and SPGPW was due to their connection with the active pockets and/or sites of ACE via hydrogen bonding, hydrophobic interaction and electrostatic force. Moreover, SEGPK, FDGPY and SPGPW could protect HUVECs by controlling levels of nitric oxide (NO) and endothelin-1 (ET-1). Therefore, this work provides an effective means for the preparation of collagens and novel ACEi peptides from monkfish swim bladders, and the prepared ACEi peptides, including SEGPK, FDGPY and SPGPW, could serve as natural functional components in the development of health care products to control hypertension.
Topics: Animals; Molecular Docking Simulation; Peptidyl-Dipeptidase A; Collagen; Fishes; Peptides; Acids; Angiotensins
PubMed: 37888451
DOI: 10.3390/md21100516 -
Signal Transduction and Targeted Therapy Feb 2024Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes multi-organ damage, which includes hepatic dysfunction, as observed in over 50% of COVID-19 patients....
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes multi-organ damage, which includes hepatic dysfunction, as observed in over 50% of COVID-19 patients. Angiotensin I converting enzyme (peptidyl-dipeptidase A) 2 (ACE2) is the primary receptor for SARS-CoV-2 entry into host cells, and studies have shown the presence of intracellular virus particles in human hepatocytes that express ACE2, but at extremely low levels. Consequently, we asked if hepatocytes might express receptors other than ACE2 capable of promoting the entry of SARS-CoV-2 into cells. To address this question, we performed a genome-wide CRISPR-Cas9 activation library screening and found that Asialoglycoprotein receptor 1 (ASGR1) promoted SARS-CoV-2 pseudovirus infection of HeLa cells. In Huh-7 cells, simultaneous knockout of ACE2 and ASGR1 prevented SARS-CoV-2 pseudovirus infection. In the immortalized THLE-2 hepatocyte cell line and primary hepatic parenchymal cells, both of which barely expressed ACE2, SARS-CoV-2 pseudovirus could successfully establish an infection. However, after treatment with ASGR1 antibody or siRNA targeting ASGR1, the infection rate significantly dropped, suggesting that SARS-CoV-2 pseudovirus infects hepatic parenchymal cells mainly through an ASGR1-dependent mechanism. We confirmed that ASGR1 could interact with Spike protein, which depends on receptor binding domain (RBD) and N-terminal domain (NTD). Finally, we also used Immunohistochemistry and electron microscopy to verify that SARS-CoV-2 could infect primary hepatic parenchymal cells. After inhibiting ASGR1 in primary hepatic parenchymal cells by siRNA, the infection efficiency of the live virus decreased significantly. Collectively, these findings indicate that ASGR1 is a candidate receptor for SARS-CoV-2 that promotes infection of hepatic parenchymal cells.
Topics: Humans; COVID-19; SARS-CoV-2; Asialoglycoprotein Receptor; HeLa Cells; Angiotensin-Converting Enzyme 2; Hepatocytes; RNA, Small Interfering
PubMed: 38355848
DOI: 10.1038/s41392-024-01754-y