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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pathogen of coronavirus disease 2019 (COVID-19), caused the outbreak escalated to pandemic. Reports suggested that near 1-3% of COVID-19 cases have a fatal outcome. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are widely used in hypertension, heart failure and chronic kidney disease. These drugs have been reported to upregulate angiotensin converting enzyme 2 (ACE2) which produces Ang (1-7), the main counter-regulatory mediator of angiotensin II. This enzyme is also known as the receptor of SARS-CoV-2 promoting the cellular uptake of the virus in the airways, however, ACE2 itself proved to be protective in several experimental models of lung injury. The present study aimed to systematically review the relationship between ACEI/ARB administration and ACE2 expression in experimental models. After a comprehensive search and selection, 27 animal studies investigating ACE2 expression in the context of ACEI and ARB were identified. The majority of these papers reported increased ACE2 levels in response to ACEI/ARB treatment. This result should be interpreted in the light of the dual role of ACE2 being a promoter of viral entry to cells and a protective factor against oxidative damage in the lungs.

Hypertension, obesity and diabetes are major risk factors associated with morbidities underlying COVID-19 infections. Regression analysis correlated presence of ACE insertion/deletion (I/D) polymorphism to COVID-19 incidence and mortality. Furthermore, COVID-19 prevalence correlated to allele frequency of angiotensin-converting enzyme (ACE) deletion (D) polymorphism within the European population.

The aim of this study was to show whether blocking the deleterious effects of neurohormonal activation from furosemide by the use of ACEI/ARBs, or the improvement of renal perfusion by using these drugs allows better diuresis and renal function preservation.

Emerging evidence suggests that renin-angiotensin system (RAS) may act as a molecular and therapeutic target for treating site-specific cancers, including prostate cancer. However, previous observational studies regarding the association between RAS inhibitors and prostate cancer risk have reported inconsistent results. We examined this association by performing a systematic review and meta-analysis. A total of 20,267 patients from nine cohort studies were enrolled. Compared with non-users of RAS inhibitors, individuals using RAS inhibitors had a reduced risk of prostate cancer (RR 0.92, 95 % CI 0.87-0.98), without statistically significant heterogeneity among studies (P = 0.118 for heterogeneity, I2 = 37.6 %). In addition, when subgroup analyses by study quality and number of cases, more statistically significant associations were observed in studies of high quality (RR 0.93, 95 % CI 0.88-0.97) and large sample size (RR 0.94, 95 % CI 0.91-0.98). There was no evidence of significant publication bias with Begg's test (P = 0.602) or with Egger's test (P = 0.350). Overall, this study indicates that use of RAS inhibitors may be associated with a decreased risk of prostate cancer. Large-scale well designed studies are needed to further explore this association.

Angiotensin-converting enzyme inhibitors are widely used for treatment of hypertension and related diseases. Here, six karnamicins E1-E6 (1-6), which bear fully substituted hydroxypyridine and thiazole moieties are characterized from the rare actinobacterium Lechevalieria rhizosphaerae NEAU-A2. Through a combination of isotopic labeling, genome mining, and enzymatic characterization studies, the programmed assembly of the fully substituted hydroxypyridine moiety in karnamicin is proposed to be due to sequential operation of a hybrid polyketide synthase-nonribosomal peptide synthetase, two regioselective pyridine ring flavoprotein hydroxylases, and a methyltransferase. Based on AlphaFold protein structures predictions, molecular docking, and site-directed mutagenesis, we find that two pyridine hydroxylases deploy active site residues distinct from other flavoprotein monooxygenases to direct the chemo- and regioselective hydroxylation of the pyridine nucleus. Pleasingly, karnamicins show significant angiotensin-converting enzyme inhibitory activity with IC50 values ranging from 0.24 to 5.81 μM, suggesting their potential use for the treatment of hypertension and related diseases.

Angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are known to cause fetal renal damage in pregnancy. Due to conflicting reports in the literature, their safety after first trimester exposure has been debated. Our aim was to determine whether the use of ACE inhibitors or ARBs in the first trimester of pregnancy is associated with an increased risk for major malformations or other adverse outcomes. All subjects were prospectively enrolled from among women contacting a teratogen information service. At initial contact, details of maternal medical history and exposures were collected and follow-up interviews were conducted to ascertain pregnancy outcomes. Two comparator groups, women with hypertension treated with other antihypertensives, and healthy controls were also recruited. Baseline maternal characteristics were not different among the three groups. There were no differences in rates of major malformations. Both the ACE-ARBs and disease-matched groups exhibited significantly lower birth weight and gestational ages than the healthy controls (P < 0.001 for both variables). There was a significantly higher rate of miscarriage noted in the ACE/ARB group (P < 0.001). These results suggest that ACE inhibitors/ARBs are not major human teratogens; however, they may be associated with an increased risk for miscarriage.

Ever since its outbreak, Corona Virus Disease 2019(COVID-19) caused by SARS-CoV-2 has affected more than 26 million individuals in more than 200 countries. Although the mortality rate of COVID-19 is low, but several clinical studies showed, patients with diabetes mellitus (DM) or other major complication at high risk of COVID-19 and reported more severe disease and increased fatality. The angiotensin-converting-enzyme 2 (ACE2), a component of renin-angiotensin-system (RAS); acts on ACE/Ang-II/AT1recptor axis, and regulates pathological processes like hypertension, cardiac dysfunction, Acute Respiratory Distress Syndrome (ARDS) etc. The progression of T2DM and hypertension show decreased expression and activity of ACE2. There are several treatment strategies for controlling diabetes, hypertension, etc; like ACE2 gene therapies, endogenous ACE2 activators, human recombinant ACE2 (hrACE2), Angiotensin-II receptor blockers (ARBs) and ACE inhibitors (ACEi) medications. ACE2, the receptors for SARS-CoV2, facilitates virus entry inside host cell. Clinicians are using two classes of medications for the treatment of COVID-19; one targets the SARS-CoV-2-ACE2 interaction, while other targets human immune system. The aim of this review is to discuss the role of ACE2 in diabetes and in COVID-19 and to provide an analysis of data proposing harm and benefit of RAS inhibitor treatment in COVID-19 infection as well as showing no association whatsoever. This review also highlights some candidate vaccines which are undergoing clinical trials.

Medications used to treat hypertension may affect fracture risk. This study investigated fracture risk for users of angiotensin converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB). Participants (899 men, median age 70.3 yr (59.9-79.1), range 50.0-96.6 yr; 574 women, median age 65.5 yr (58.1-75.4), range 50.1-94.6 yr) were from the Geelong Osteoporosis Study. Medication use was self-reported and incident fractures were ascertained using radiological reports. Bone mineral density (BMD) was measured at the femoral neck. Participants were divided into four groups: (1) non-users without hypertension, (2) non-users with hypertension, (3) ACEI users and (4) ARB users. Dosage was calculated using the defined daily dose (DDD) criteria. Participants were followed from date of visit to first fracture, death or 31 December 2016, whichever occurred first. Cox proportional hazards models were used for analyses. At least one incident fracture was sustained by 156 men and 135 women over a median(IQR) of 11.5(6.2-13.2) and 10.9(6.3-11.6) years of follow-up, respectively. In unadjusted analyses, compared to non-users without hypertension, men in all three other groups had a higher risk of fracture (Hazard Ratio (HR, 95%CI) 1.54, 1.00-2.37; 1.90, 1.18-3.05; 2.15, 1.26-3.66), for non-users with hypertension, ACEI and ARB users, respectively). Following adjustment for age, prior fracture and BMD, these associations became non-significant. A dose effect for ARB use was observed; men using lower doses had a higher risk of fracture than non-users without hypertension, in both unadjusted (2.66, 1.34-5.29) and adjusted (2.03, 1.01-4.08) analyses, but this association was not observed at higher doses. For women, unadjusted analyses showed a higher risk for ACEI users compared to non-users without hypertension (1.74, 1.07-2.83). This was explained after adjustment for age, alcohol consumption, prior fracture and BMD (1.28, 0.74-2.22). No other differences were observed. In men, lower dose (0 < DDD ≤ 1) ARB use was associated with an increased risk of fracture. ACEI or ARB use was not associated with increased risk of incident fracture in women. These findings may be important for antihypertensive treatment decisions in individuals with a high risk of fracture.

Spondyloarthritis (SpA) is a chronic inflammatory disease that results in bone ankylosis. The tissue renin-angiotensin system (RAS) is an emerging pathway potentially implicated in SpA-associated bone changes. The aim of the present study was to determine the mechanisms underlying this relationship. Sakaguchi (SKG) mice injected with curdlan (SKGc), animal models for SpA, were treated with RAS modulators, angiotensin II receptor blockers (ARBs) or angiotensin-converting enzyme inhibitors (ACEis). Disease activity was assessed using clinical scores and computed tomography scans. Mouse primary bone marrow monocytes (BMMs), osteoblast (OB) progenitor cells, peripheral blood monocytes (PBMCs), and bone-derived cells (BdCs) from patients with radiographic axial SpA (r-axSpA) were used to investigate the role of RAS in SpA pathogenesis. The expression of RAS components was significantly increased in SKGc mouse joints, and ARBs significantly reduced erosion and systemic bone loss, whereas ACEis did not. Osteoclast (OC) differentiation from primary BMMs, mediated by TRAF6, was inhibited by ARBs but promoted by ACEis; the modulators also exerted opposite effects on OB differentiation. Expression of RAS molecules was higher in PBMCs and BdCs of patients with r-axSpA than in control participants. ARBs inhibited OB differentiation in the BdCs of patients with r-axSpA, whereas ACEis did not. Neither ARBs nor ACEis affected OB differentiation in the control participants. In SpA, a condition characterized by RAS overexpression, ARBs, but not ACEis, inhibited OC and OB differentiation and bone progression. The findings should be taken into account when treating patients with SpA using RAS modulators.

Background Use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (ACEi/ARB) is thought to affect COVID-19 through modulating levels of angiotensin-converting enzyme 2, the cell entry receptor for SARS-CoV2. We sought to assess the association between ACEi/ARB, biomarkers of inflammation, and outcomes in patients hospitalized for COVID-19. Methods and Results We leveraged the ISIC (International Study of Inflammation in COVID-19), identified patients admitted for symptomatic COVID-19 between February 1, 2020 and June 1, 2021 for COVID-19, and examined the association between in-hospital ACEi/ARB use and all-cause death, need for ventilation, and need for dialysis. We estimated the causal effect of ACEi/ARB on the composite outcomes using marginal structural models accounting for serial blood pressure and serum creatinine measures. Of 2044 patients in ISIC, 1686 patients met inclusion criteria, of whom 398 (23.6%) patients who were previously on ACEi/ARB received at least 1 dose during their hospitalization for COVID-19. There were 215 deaths, 407 patients requiring mechanical ventilation, and 124 patients who required dialysis during their hospitalization. Prior ACEi/ARB use was associated with lower levels of soluble urokinase plasminogen activator receptor and C-reactive protein. In multivariable analysis, in-hospital ACEi/ARB use was associated with a lower risk of the composite outcome of in-hospital death, mechanical ventilation, or dialysis (adjusted hazard ratio 0.49, 95% CI [0.36-0.65]). Conclusions In patients hospitalized for COVID-19, ACEi/ARB use was associated with lower levels of inflammation and lower risk of in-hospital outcomes. Clinical trials will define the role of ACEi/ARB in the treatment of COVID-19. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04818866.

The present study was designed to investigate cognitive enhancing property of angiotensin-converting enzymes inhibitors (ACEI) and angiotensin receptor blockers (ARBs) in rats.

Outbreak of coronavirus disease 2019 occurred in Wuhan and has rapidly spread to almost all parts of world. GB-1, the herbal formula from Tian Shang Sheng Mu of Chiayi Puzi Peitian Temple, is used for the prophylaxis of SARS-CoV-2 in Taiwan. In this study, we investigated that the effect of GB-1 and the index compounds of GB-1 on the ACE2 and TMPRSS2 expression through in vitro and in vivo study. In our result, GB-1 can inhibit ACE2 and TMPRSS2 protein expression in HepG2 cells, 293T cells, and Caco-2 cells without cytotoxicity. For the mouse model, GB-1 treatment could decrease ACE2 and TMPRSS2 expression levels of the lung and kidney tissue without adverse effects, including nephrotoxicity and hepatotoxicity. In the compositions of GB-1, 0.5-1 mg/ml of Glycyrrhiza uralensis Fisch. ex DC. extract could not inhibit ACE2 mRNA and protein expression in HepG2 cells. In addition, theaflavin-3-gallate could inhibit protein expression of ACE2 and TMPRSS2 without significant cytotoxicity. Our results suggest that GB-1 and theaflavin-3-gallate could act as potential candidates for prophylaxis or treatment of SARS-CoV-2 infection through inhibiting protein expression of ACE2 and TMPRSS2 for the further study.

Some studies suggest that angiotensin II type 1 receptor blockers (ARBs) may protect against memory decline more than angiotensin-converting enzyme inhibitors (ACE-Is), but few have examined possible mechanisms. We assessed longitudinal differences between ARB versus ACE-I users in global and sub-regional amyloid-β accumulation by 18F-florbetapir. In cognitively normal older adults (n= 142), propensity-weighted linear mixed-effects models showed that ARB versus ACE-I use was associated with slower amyloid-β accumulation in the cortex, and specifically in the caudal anterior cingulate and precuneus, and in the precentral and postcentral gyri. In amyloid-positive participants with Alzheimer's disease dementia or mild cognitive impairment (n = 169), ARB versus ACE-I use was not associated with different rates of amyloid-β accumulation. Apolipoprotein E ε4 carrier status explained some heterogeneity in the different rates of amyloid-β accumulation between users of ARBs versus ACE-Is in the study. Replicative studies and clinical trials are warranted to confirm potential benefits of ARBs on rates of amyloid-β accumulation in the contexts of Alzheimer's disease prevention and treatment.

Patients with heart failure were affected severely by COVID-19. Most heart failure patients are on guideline directed medical therapy, which includes ACE inhibitors (ACEI) and ARBs. These medications were controversial at the beginning of the pandemic due to their interplay with the receptor that SARS-CoV-2 binds in the lungs. We investigated the effect that ACEI and ARB had on patients with hypertension, coronary artery disease, and heart failure.

Preclinical studies suggested that pharmacological inhibition of the renin-angiotensin-aldosterone system (RAAS) by ACE inhibitors (ACEis) or angiotensin II receptor blockers (ARBs) may increase local angiotensin-converting enzyme 2 (ACE2) expression.

At present, anti-angiogenic drugs (AADs) are widely used in the systemic treatment of hepatocellular carcinoma (HCC) or other types of cancer, and have achieved good anti-cancer effect, whereas treatment-related proteinuria can affect the routine use of AADs, which in turn abates the overall efficacy. Currently, most clinicians prescribe angiotensin-converting enzyme inhibitors (ACEIs) to alleviate proteinuria according to diabetic nephropathy guidelines or expert recommendations. However, the efficacy of ACEIs in reducing AAD-related proteinuria and its effect on the anticancer effect of AADs is unknown. Our clinical data showed that some HCC patients experienced tumor progression by ACEIs administration for the treatment of proteinuria caused by AADs. Here, we confirmed that in different tumor-bearing mouse models, ACEIs did not delay the appearance of proteinuria or alleviate proteinuria caused by AADs but compromised the anticancer efficacy of AADs. This effect is unrelated to the change in the VEGF signaling pathway. Our data showed that the combination of ACEIs and AADs flared the production of kidney-derived erythropoietin (EPO). In turn, EPO compromises the anti-angiogenic effects of AADs and decreases antitumor activity. In conclusion, for the treatment of proteinuria caused by AADs, ACEIs have no efficacy while also promoting AADs resistance. This finding is of great significance to guide clinical standardized management of side effects of anti-angiogenic therapy for cancer patients.

Over the years, coronaviruses (CoV) have posed a severe public health threat, causing an increase in mortality and morbidity rates throughout the world. The recent outbreak of a novel coronavirus, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the current Coronavirus Disease 2019 (COVID-19) pandemic that affected more than 215 countries with over 23 million cases and 800,000 deaths as of today. The situation is critical, especially with the absence of specific medicines or vaccines; hence, efforts toward the development of anti-COVID-19 medicines are being intensively undertaken. One of the potential therapeutic targets of anti-COVID-19 drugs is the angiotensin-converting enzyme 2 (ACE2). ACE2 was identified as a key functional receptor for CoV associated with COVID-19. ACE2, which is located on the surface of the host cells, binds effectively to the spike protein of CoV, thus enabling the virus to infect the epithelial cells of the host. Previous studies showed that certain flavonoids exhibit angiotensin-converting enzyme inhibition activity, which plays a crucial role in the regulation of arterial blood pressure. Thus, it is being postulated that these flavonoids might also interact with ACE2. This postulation might be of interest because these compounds also show antiviral activity in vitro. This article summarizes the natural flavonoids with potential efficacy against COVID-19 through ACE2 receptor inhibition.

Interest exists concerning the use of angiotensin-converting enzyme inhibitors (ACEis) in patients with COVID-19 disease.

To investigate whether endogenous bradykinin is involved in the antioxidant action of angiotensin-converting enzyme inhibitors (ACEIs) in acute hyperglycemia.