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      Regulation of Angiotensin- Converting Enzyme 2 in Obesity: Implications for COVID-19

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          Abstract

          The ongoing COVID-19 pandemic is caused by the novel coronavirus SARS-CoV-2. Age, smoking, obesity, and chronic diseases such as cardiovascular disease and diabetes have been described as risk factors for severe complications and mortality in COVID-19. Obesity and diabetes are usually associated with dysregulated lipid synthesis and clearance, which can initiate or aggravate pulmonary inflammation and injury. It has been shown that for viral entry into the host cell, SARS-CoV-2 utilizes the angiotensin-converting enzyme 2 (ACE2) receptors present on the cells. We aimed to characterize how SARS-CoV-2 dysregulates lipid metabolism pathways in the host and the effect of dysregulated lipogenesis on the regulation of ACE2, specifically in obesity. In our study, through the re-analysis of publicly available transcriptomic data, we first found that lung epithelial cells infected with SARS-CoV-2 showed upregulation of genes associated with lipid metabolism, including the SOC3 gene, which is involved in the regulation of inflammation and inhibition of leptin signaling. This is of interest as viruses may hijack host lipid metabolism to allow the completion of their viral replication cycles. Furthermore, a dataset using a mouse model of diet-induced obesity showed a significant increase in Ace2 expression in the lungs, which negatively correlated with the expression of genes that code for sterol response element-binding proteins 1 and 2 (SREBP). Suppression of Srebp1 showed a significant increase in Ace2 expression in the lung. Moreover, ACE2 expression in human subcutaneous adipose tissue can be regulated through changes in diet. Validation of the in silico data revealed a higher expression of ACE2, TMPRSS2 and SREBP1 in vitro in lung epithelial cells from obese subjects compared to non-obese subjects. To our knowledge this is the first study to show upregulation of ACE2 and TMPRSS2 in obesity. In silico and in vitro results suggest that the dysregulated lipogenesis and the subsequently high ACE2 expression in obese patients might be the mechanism underlying the increased risk for severe complications in those patients when infected by SARS-CoV-2.

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          Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

          Summary Background A recent cluster of pneumonia cases in Wuhan, China, was caused by a novel betacoronavirus, the 2019 novel coronavirus (2019-nCoV). We report the epidemiological, clinical, laboratory, and radiological characteristics and treatment and clinical outcomes of these patients. Methods All patients with suspected 2019-nCoV were admitted to a designated hospital in Wuhan. We prospectively collected and analysed data on patients with laboratory-confirmed 2019-nCoV infection by real-time RT-PCR and next-generation sequencing. Data were obtained with standardised data collection forms shared by WHO and the International Severe Acute Respiratory and Emerging Infection Consortium from electronic medical records. Researchers also directly communicated with patients or their families to ascertain epidemiological and symptom data. Outcomes were also compared between patients who had been admitted to the intensive care unit (ICU) and those who had not. Findings By Jan 2, 2020, 41 admitted hospital patients had been identified as having laboratory-confirmed 2019-nCoV infection. Most of the infected patients were men (30 [73%] of 41); less than half had underlying diseases (13 [32%]), including diabetes (eight [20%]), hypertension (six [15%]), and cardiovascular disease (six [15%]). Median age was 49·0 years (IQR 41·0–58·0). 27 (66%) of 41 patients had been exposed to Huanan seafood market. One family cluster was found. Common symptoms at onset of illness were fever (40 [98%] of 41 patients), cough (31 [76%]), and myalgia or fatigue (18 [44%]); less common symptoms were sputum production (11 [28%] of 39), headache (three [8%] of 38), haemoptysis (two [5%] of 39), and diarrhoea (one [3%] of 38). Dyspnoea developed in 22 (55%) of 40 patients (median time from illness onset to dyspnoea 8·0 days [IQR 5·0–13·0]). 26 (63%) of 41 patients had lymphopenia. All 41 patients had pneumonia with abnormal findings on chest CT. Complications included acute respiratory distress syndrome (12 [29%]), RNAaemia (six [15%]), acute cardiac injury (five [12%]) and secondary infection (four [10%]). 13 (32%) patients were admitted to an ICU and six (15%) died. Compared with non-ICU patients, ICU patients had higher plasma levels of IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα. Interpretation The 2019-nCoV infection caused clusters of severe respiratory illness similar to severe acute respiratory syndrome coronavirus and was associated with ICU admission and high mortality. Major gaps in our knowledge of the origin, epidemiology, duration of human transmission, and clinical spectrum of disease need fulfilment by future studies. Funding Ministry of Science and Technology, Chinese Academy of Medical Sciences, National Natural Science Foundation of China, and Beijing Municipal Science and Technology Commission.
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            SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

            Summary The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.
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              Renin–Angiotensin–Aldosterone System Inhibitors in Patients with Covid-19

              The renin–angiotensin–aldosterone system (RAAS) is an elegant cascade of vasoactive peptides that orchestrate key processes in human physiology. Severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) and SARS-CoV-2, which have been responsible for the SARS epidemic in 2002 to 2004 and for the more recent coronavirus disease 2019 (Covid-19) pandemic, respectively, interface with the RAAS through angiotensin-converting enzyme 2 (ACE2), an enzyme that physiologically counters RAAS activation but also functions as a receptor for both SARS viruses. 1,2 The interaction between the SARS viruses and ACE2 has been proposed as a potential factor in their infectivity, 3,4 and there are concerns about the use of RAAS inhibitors that may alter ACE2 and whether variation in ACE2 expression may be in part responsible for disease virulence in the ongoing Covid-19 pandemic. 5-8 Indeed, some media sources and health systems have recently called for the discontinuation of ACE inhibitors and angiotensin-receptor blockers (ARBs), both prophylactically and in the context of suspected Covid-19. Given the common use of ACE inhibitors and ARBs worldwide, guidance on the use of these drugs in patients with Covid-19 is urgently needed. Here, we highlight that the data in humans are too limited to support or refute these hypotheses and concerns. Specifically, we discuss the uncertain effects of RAAS blockers on ACE2 levels and activity in humans, and we propose an alternative hypothesis that ACE2 may be beneficial rather than harmful in patients with lung injury. We also explicitly raise the concern that withdrawal of RAAS inhibitors may be harmful in certain high-risk patients with known or suspected Covid-19. Covid-19 and Older Adults with Coexisting Conditions Initial reports 5-8 have called attention to the potential overrepresentation of hypertension among patients with Covid-19. In the largest of several case series from China that have been released during the Covid-19 pandemic (Table S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org), hypertension was the most frequent coexisting condition in 1099 patients, with an estimated prevalence of 15% 9 ; however, this estimate appears to be lower than the estimated prevalence of hypertension seen with other viral infections 10 and in the general population in China. 11,12 Coexisting conditions, including hypertension, have consistently been reported to be more common among patients with Covid-19 who have had severe illness, been admitted to the intensive care unit, received mechanical ventilation, or died than among patients who have had mild illness. There are concerns that medical management of these coexisting conditions, including the use of RAAS inhibitors, may have contributed to the adverse health outcomes observed. However, these conditions appear to track closely with advancing age, 13 which is emerging as the strongest predictor of Covid-19–related death. 14 Unfortunately, reports to date have not rigorously accounted for age or other key factors that contribute to health as potential confounders in risk prediction. With other infective illnesses, coexisting conditions such as hypertension have been key prognostic determinants, 10 and this also appears to be the case with Covid-19. 15 It is important to note that, despite inferences about the use of background RAAS inhibitors, specific details have been lacking in studies (Table S1). Population-based studies have estimated that only 30 to 40% of patients in China who have hypertension are treated with any antihypertensive therapy; RAAS inhibitors are used alone or in combination in 25 to 30% of these treated patients. 11,12 Given such estimates, only a fraction of patients with Covid-19, at least in China, are anticipated to have been previously treated with RAAS inhibitors. Data showing patterns of use of RAAS inhibitors and associated health outcomes that rigorously account for treatment indication and illness severity among patients with Covid-19 are needed. Uncertain Effects of RAAS Inhibitors on ACE2 in Humans Tissue-specific and circulating components of the RAAS make up a complex intersecting network of regulatory and counterregulatory peptides (Figure 1). ACE2 is a key counterregulatory enzyme that degrades angiotensin II to angiotensin-(1–7), thereby attenuating its effects on vasoconstriction, sodium retention, and fibrosis. Although angiotensin II is the primary substrate of ACE2, that enzyme also cleaves angiotensin I to angiotensin-(1–9) and participates in the hydrolysis of other peptides. 16 In studies in humans, tissue samples from 15 organs have shown that ACE2 is expressed broadly, including in the heart and kidneys, as well as on the principal target cells for SARS-CoV-2 (and the site of dominant injury), the lung alveolar epithelial cells. 17 Of interest, the circulating levels of soluble ACE2 are low and the functional role of ACE2 in the lungs appears to be relatively minimal under normal conditions 18 but may be up-regulated in certain clinical states. Because ACE inhibitors and ARBs have different effects on angiotensin II, the primary substrate of ACE2, the effects of these agents on ACE2 levels and activity may be anticipated to differ. Despite substantial structural homology between ACE and ACE2, their enzyme active sites are distinct. As a result, ACE inhibitors in clinical use do not directly affect ACE2 activity. 19 Experimental animal models have shown mixed findings with respect to the effects of ACE inhibitors on ACE2 levels or activity in tissue. 20-25 Similarly, animal models have had inconsistent findings with respect to the effects of ARBs on ACE2, with some showing that ARBs may increase messenger RNA expression or protein levels of ACE2 in tissue 21,26-34 and others showing no effect. 23 In contrast to available animal models, there are few studies in humans regarding the effects of RAAS inhibition on ACE2 expression. In one study, the intravenous administration of ACE inhibitors in patients with coronary artery disease did not influence angiotensin-(1–7) production, a finding that calls into question whether ACE inhibitors have any direct effects on ACE2-directed angiotensin II metabolism. 35 Similarly, in another study, among patients with hypertension, angiotensin-(1–7) levels appeared to be unaffected after initial treatment with the ACE inhibitor captopril; however, with exposure to captopril monotherapy over a period of 6 months, angiotensin-(1–7) levels increased. 36 Furthermore, few studies have examined plasma ACE2 activity or urinary ACE2 levels in patients who have received long-term treatment with RAAS inhibitors. In cross-sectional studies involving patients with heart failure, 37 atrial fibrillation, 38 aortic stenosis, 39 and coronary artery disease, 40 plasma ACE2 activity was not higher among patients who were taking ACE inhibitors or ARBs than among untreated patients. In a longitudinal cohort study involving Japanese patients with hypertension, urinary ACE2 levels were higher among patients who received long-term treatment with the ARB olmesartan than among untreated control patients, but that association was not observed with the ACE inhibitor enalapril or with other ARBs (losartan, candesartan, valsartan, and telmisartan). 41 Previous treatment with ACE inhibitors was associated with increased intestinal messenger RNA levels of ACE2 in one study, but that association was not observed with ARBs 25 ; data are lacking regarding the effects of RAAS inhibitors on lung-specific expression of ACE2. These seemingly conflicting data indicate the complexity underlying RAAS responses to pathway modulators and reinforce the concept that findings from preclinical models may not readily translate to human physiology. Such data do suggest that effects on ACE2 should not be assumed to be uniform across RAAS inhibitors or even in response to therapies within a given drug class. 41 It is important to note that the plasma ACE2 level may not be a reliable indicator of the activity of the full-length membrane-bound form, in part because ACE2 is shed from the membrane, a process that appears to be separately regulated by an endogenous inhibitor. 42 In addition to the degree of expression, the biologic relevance of ACE2 may vary according to tissue and clinical state. Unfortunately, data showing the effects of ACE inhibitors, ARBs, and other RAAS inhibitors on lung-specific expression of ACE2 in experimental animal models and in humans are lacking. Furthermore, even if RAAS inhibitors modify ACE2 levels or activity (or both) in target tissue beds, clinical data are lacking to indicate whether this would in turn facilitate greater engagement and entry of SARS-CoV-2 spike protein. Further mechanistic studies in humans are needed to better define the unique interplay between SARS-CoV-2 and the RAAS network. Potential for Benefit Rather Than Harm of RAAS Blockers in Covid-19 SARS-CoV-2 appears not only to gain initial entry through ACE2 but also to subsequently down-regulate ACE2 expression such that the enzyme is unable to exert protective effects in organs. It has been postulated but unproven that unabated angiotensin II activity may be in part responsible for organ injury in Covid-19. 43,44 After the initial engagement of SARS-CoV-2 spike protein, there is subsequent down-regulation of ACE2 abundance on cell surfaces. 45 Continued viral infection and replication contribute to reduced membrane ACE2 expression, at least in vitro in cultured cells. 46 Down-regulation of ACE2 activity in the lungs facilitates the initial neutrophil infiltration in response to bacterial endotoxin 47 and may result in unopposed angiotensin II accumulation and local RAAS activation. Indeed, in experimental mouse models, exposure to SARS-CoV-1 spike protein induced acute lung injury, which is limited by RAAS blockade. 45 Other mouse models have suggested that dysregulation of ACE2 may mediate acute lung injury that is secondary to virulent strains of influenza 48,49 and respiratory syncytial virus. 50 In a small study, patients with Covid-19 appeared to have elevated levels of plasma angiotensin II, which were in turn correlated with total viral load and degree of lung injury. 44 Restoration of ACE2 through the administration of recombinant ACE2 appeared to reverse this devastating lung-injury process in preclinical models of other viral infections 49,50 and safely reduced angiotensin II levels in a phase 2 trial evaluating acute respiratory distress syndrome in humans. 51 Dysregulated ACE2 may theoretically also attenuate cardioprotection in the context of myocardial involvement and abnormal pulmonary hemodynamics 52,53 in Covid-19. Markers of myocardial injury have been shown to be elevated during the disease course of Covid-19 54 and to increase rapidly with clinical deterioration and preceding death. 14 Many viruses are cardiotropic, and subclinical viral myocarditis is commonly seen in viremia associated with a wide range of infectious agents. ACE2 has a well-recognized role in myocardial recovery and injury response; in one study, ACE2 knockout in animal models contributed to adverse left ventricular remodeling in response to acute injury driven by angiotensin II. 55 In autopsies of patients who died from SARS, 35% of heart samples showed the presence of viral RNA, which in turn was associated with reduced ACE2 protein expression. 56 Administration of recombinant ACE2 normalizes angiotensin II levels in human explanted hearts with dilated cardiomyopathy. 57 These hypotheses have prompted trials to test whether the provision of recombinant ACE2 protein may be beneficial in restoring balance to the RAAS network and potentially preventing organ injury (ClinicalTrials.gov number, NCT04287686). In addition, paired trials of losartan as a treatment for Covid-19 are being conducted among patients who have not previously received treatment with a RAAS inhibitor and are either hospitalized (NCT04312009) or not hospitalized (NCT04311177). Maintenance of RAAS Inhibitors with Known or Suspected Covid-19 Despite these theoretical uncertainties regarding whether pharmacologic regulation of ACE2 may influence the infectivity of SARS-CoV-2, there is clear potential for harm related to the withdrawal of RAAS inhibitors in patients in otherwise stable condition. Covid-19 is particularly severe in patients with underlying cardiovascular diseases, 9 and in many of these patients, active myocardial injury, 14,54,58-60 myocardial stress, 59 and cardiomyopathy 59 develop during the course of illness. RAAS inhibitors have established benefits in protecting the kidney and myocardium, and their withdrawal may risk clinical decompensation in high-risk patients. Although rates of heart failure have been infrequently reported in epidemiologic reports from China to date, the prevalence of heart failure among critically ill patients with Covid-19 in the United States may be high (>40%). 59 In the Quinapril Heart Failure Trial, among patients with chronic symptomatic heart failure, withdrawal of quinapril resulted in a progressive decline in clinical status. 61 In the TRED-HF trial, among asymptomatic patients with heart failure with recovered left ventricular ejection fraction, the phased withdrawal of medical therapy (including RAAS inhibitors) resulted in rapid relapse of dilated cardiomyopathy. 62 In addition, RAAS inhibitors are a cornerstone of therapy after myocardial infarction: maintenance of therapy in the days to weeks after the index event has been shown to reduce early mortality. 63 Among patients with unstable clinical status, myocardial injury associated with Covid-19 may pose even higher early risks after withdrawal of RAAS inhibitors. Withdrawal of RAAS inhibitors that are being administered for the management of hypertension may be less risky than withdrawal of RAAS inhibitors that are being administered for conditions in which they are considered guideline-directed therapy but may be associated with other challenges. Switching from a RAAS inhibitor to another antihypertensive therapy in a stable ambulatory patient may require careful follow-up to avoid rebound increases in blood pressure. In addition, selection of dose-equivalent antihypertensive therapies may be challenging in practice and may be patient-dependent. Even small and short-lived periods of blood pressure instability after a therapeutic change have been associated with excess cardiovascular risk. 64-66 This may be an especially important consideration in patients with Covid-19, which appears to result in a state of RAAS activation, 44 and in settings (e.g., China) where baseline blood-pressure control is infrequently reached at the population level. 11,12 The effects of withdrawing RAAS inhibitors or switching treatments are uncertain among patients with chronic kidney disease. Although reported rates of chronic kidney disease appear to be low among hospitalized patients with Covid-19 in China (1 to 3%) (Table S1), the prevalence may be higher among patients who are critically ill and among those in other geographic regions. 59 Many patients have varying degrees of acute kidney injury during illness. 14,67,68 For these high-risk patients, individualized treatment decisions regarding the maintenance of RAAS inhibitors that are guided by hemodynamic status, renal function, and clinical stability are recommended. On the basis of the available evidence, we think that, despite the theoretical concerns and uncertainty regarding the effect of RAAS inhibitors on ACE2 and the way in which these drugs might affect the propensity for or severity of Covid-19, RAAS inhibitors should be continued in patients in otherwise stable condition who are at risk for, are being evaluated for, or have Covid-19 (see text box), a position now supported by multiple specialty societies (Table S2). Although additional data may further inform the treatment of high-risk patients with Covid-19, clinicians need to be cognizant of the unintended consequences of prematurely discontinuing proven therapies in response to hypothetical concerns that may be based on incomplete experimental evidence. 69 Key Points Related to the Interplay between Covid-19 and the Renin–Angiotensin–Aldosterone System • ACE2, an enzyme that physiologically counters RAAS activation, is the functional receptor to SARS-CoV-2, the virus responsible for the Covid-19 pandemic • Select preclinical studies have suggested that RAAS inhibitors may increase ACE2 expression, raising concerns regarding their safety in patients with Covid-19 • Insufficient data are available to determine whether these observations readily translate to humans, and no studies have evaluated the effects of RAAS inhibitors in Covid-19 • Clinical trials are under way to test the safety and efficacy of RAAS modulators, including recombinant human ACE2 and the ARB losartan in Covid-19 • Abrupt withdrawal of RAAS inhibitors in high-risk patients, including those who have heart failure or have had myocardial infarction, may result in clinical instability and adverse health outcomes • Until further data are available, we think that RAAS inhibitors should be continued in patients in otherwise stable condition who are at risk for, being evaluated for, or with Covid-19
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                Author and article information

                Contributors
                Journal
                Front Physiol
                Front. Physiol.
                Frontiers in Physiology
                Frontiers Media S.A.
                1664-042X
                18 September 2020
                2020
                18 September 2020
                : 11
                Affiliations
                1College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences , Dubai, United Arab Emirates
                2Meakins-Christie Laboratories, Research Institute of the McGill University Health Center , Montreal, QC, Canada
                3Al Jalila Children’s Specialty Hospital , Dubai, United Arab Emirates
                4Sharjah Institute for Medical Research, College of Medicine, University of Sharjah , Sharjah, United Arab Emirates
                Author notes

                Edited by: Dmitri Samovski, Washington University School of Medicine in St. Louis, United States

                Reviewed by: David Bernlohr, University of Minnesota Twin Cities, United States; Daniele Vergara, University of Salento, Italy

                *Correspondence: Qutayba Hamid, qalheialy@ 123456sharjah.ac.ae

                This article was submitted to Lipid and Fatty Acid Research, a section of the journal Frontiers in Physiology

                Article
                10.3389/fphys.2020.555039
                7531362
                Copyright © 2020 Al Heialy, Hachim, Senok, Gaudet, Abou Tayoun, Hamoudi, Alsheikh-Ali and Hamid.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 10, Tables: 3, Equations: 0, References: 48, Pages: 13, Words: 0
                Categories
                Physiology
                Original Research

                Anatomy & Physiology

                obesity, ace2, covid-19, sars-cov-2, lipid metabolism

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