{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T12:31:59Z","timestamp":1777120319914,"version":"3.51.4"},"reference-count":46,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2020,10,8]],"date-time":"2020-10-08T00:00:00Z","timestamp":1602115200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100006662","name":"NIHR","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006662","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Biomedical Research Centre Funding Scheme"},{"name":"NHS"},{"DOI":"10.13039\/501100000276","name":"Department of Health and Social Care","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000276","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,9,12]]},"abstract":"<jats:title>Summary<\/jats:title>\n               <jats:p>Coronavirus disease 2019 (COVID-19) has presented physicians with an unprecedented number of challenges and mortality. The basic question is why, in contrast to other \u2018respiratory\u2019 viruses, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can result in such multi-systemic, life-threatening complications and a severe pulmonary vasculopathy. It is widely known that SARS-CoV-2 uses membrane-bound angiotensin-converting enzyme 2 (ACE2) as a receptor, resulting in internalization of the complex by the host cell. We discuss the evidence that failure to suppress coronaviral replication within 5\u2009days results in sustained downregulation of ACE2 protein expression and that ACE2 is under negative-feedback regulation. We then expose openly available experimental repository data that demonstrate the gene for ACE2 lies in a novel cluster of inter-regulated genes on the X chromosome including PIR encoding pirin (quercetin 2,3-dioxygenase), and VEGFD encoding the predominantly lung-expressed vascular endothelial growth factor D. The five double-elite enhancer\/promoters pairs that are known to be operational, and shared read-through lncRNA transcripts, imply that ongoing SARS-CoV-2 infection will reduce host defences to reactive oxygen species, directly generate superoxide O2\u00b7\u2212 and H2O2 (a \u2018 ROS storm\u2019), and impair pulmonary endothelial homeostasis. Published cellular responses to oxidative stress complete the loop to pathophysiology observed in severe COVID-19. Thus, for patients who fail to rapidly suppress viral replication, the newly appreciated ACE2 co-regulated gene cluster predicts delayed responses that would account for catastrophic deteriorations. We conclude that ACE2 homeostatic drives provide a unified understanding that should help optimize therapeutic approaches during the wait until safe, effective vaccines and antiviral therapies for SARS-CoV-2 are delivered.<\/jats:p>","DOI":"10.1093\/qjmed\/hcaa241","type":"journal-article","created":{"date-parts":[[2020,8,4]],"date-time":"2020-08-04T19:16:28Z","timestamp":1596568588000},"page":"629-634","source":"Crossref","is-referenced-by-count":6,"title":["Vascular inflammation and endothelial injury in SARS-CoV-2 infection: the overlooked regulatory cascades implicated by the <i>ACE2<\/i> gene cluster"],"prefix":"10.1093","volume":"116","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9007-5775","authenticated-orcid":false,"given":"C L","family":"Shovlin","sequence":"first","affiliation":[{"name":"From National Heart and Lung Institute, Imperial College London , London, UK"},{"name":"Respiratory Medicine, Imperial College Healthcare NHS Trust , London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7894-873X","authenticated-orcid":false,"given":"M P","family":"Vizcaychipi","sequence":"additional","affiliation":[{"name":"Department of Intensive Care, Chelsea & Westminster NHS Foundation Trust , London, UK"},{"name":"Department of Surgery and Cancer, Imperial College London , London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2020,10,8]]},"reference":[{"key":"2023091218074678200_hcaa241-B1","author":"Johns Hopkins University Center for Systems Science and Engineering (CSSE)","year":"2020"},{"key":"2023091218074678200_hcaa241-B2","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1016\/S0140-6736(20)30566-3","article-title":"Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study","volume":"395","author":"Zhou","year":"2020","journal-title":"Lancet"},{"key":"2023091218074678200_hcaa241-B3","doi-asserted-by":"crossref","DOI":"10.1016\/j.bjid.2020.07.010","article-title":"Increase in COVID-19 inpatient survival following detection of Thromboembolic and Cytokine storm risk from the point of admission to hospital by a near real time Traffic-light System (TraCe-Tic)","volume-title":"Braz J Infect Dis","author":"Vizcaychipi"},{"key":"2023091218074678200_hcaa241-B4","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1186\/s13054-020-03077-0","article-title":"The unique characteristics of COVID-19 coagulopathy","volume":"24","author":"Iba","year":"2020","journal-title":"Crit Care"},{"key":"2023091218074678200_hcaa241-B5","article-title":"Pulmonary angiopathy in severe COVID-19: physiologic, imaging and hematologic observations","author":"Patel","journal-title":"Am J Respir Crit Care Med"},{"key":"2023091218074678200_hcaa241-B6","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1016\/S2213-2600(20)30243-5","article-title":"Vander Heide RS. 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