{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T17:44:14Z","timestamp":1787161454172,"version":"build-2736575974"},"reference-count":97,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,8,17]],"date-time":"2021-08-17T00:00:00Z","timestamp":1629158400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Angiotensin-Converting Enzyme 2 (ACE2) is an 805 amino acid protein encoded by the ACE2 gene expressed in various human cells, especially in those located in the epithelia. The primary function of ACE2 is to produce angiotensin (1\u20137) from angiotensin II (Ang II). The current research has described the importance of ACE2 and Ang (1\u20137) in alternative routes of the renin-angiotensin system (RAS) that promote the downregulation of fibrosis, inflammation, and oxidative stress processes in a great variety of diseases, such as hypertension, acute lung injury, liver cirrhosis, and kidney abnormalities. Investigations into the recent outbreak of the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have revealed the importance of ACE2 during infection and its role in recognizing viral binding proteins through interactions with specific amino acids of this enzyme. Additionally, the ACE2 expression in several organs has allowed us to understand the clinical picture related to the infection caused by SARS-CoV-2. This review aims to provide context for the functions and importance of ACE2 with regards to SARS-CoV-2 in the general clinical aspect and its impact on other diseases, especially respiratory diseases.<\/jats:p>","DOI":"10.3390\/ph14080805","type":"journal-article","created":{"date-parts":[[2021,8,17]],"date-time":"2021-08-17T21:27:40Z","timestamp":1629235660000},"page":"805","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Angiotensin-Converting Enzyme 2 (ACE2) in the Context of Respiratory Diseases and Its Importance in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1240-0637","authenticated-orcid":false,"given":"Enrique","family":"Ambrocio-Ortiz","sequence":"first","affiliation":[{"name":"HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cos\u00edo Villegas, Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gloria","family":"P\u00e9rez-Rubio","sequence":"additional","affiliation":[{"name":"HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cos\u00edo Villegas, Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4464-4396","authenticated-orcid":false,"given":"Alma","family":"Del \u00c1ngel-Pablo","sequence":"additional","affiliation":[{"name":"HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cos\u00edo Villegas, Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2825-506X","authenticated-orcid":false,"given":"Ivette","family":"Buend\u00eda-Rold\u00e1n","sequence":"additional","affiliation":[{"name":"Translational Research Laboratory on Aging and Pulmonary Fibrosis, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas, Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2334-0361","authenticated-orcid":false,"given":"Leslie","family":"Ch\u00e1vez-Gal\u00e1n","sequence":"additional","affiliation":[{"name":"Laboratory of Integrative Immunology, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas, Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael","family":"Hern\u00e1ndez-Zenteno","sequence":"additional","affiliation":[{"name":"Tobacco Smoking and COPD Research Department, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas, Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandra","family":"Ram\u00edrez-Venegas","sequence":"additional","affiliation":[{"name":"Tobacco Smoking and COPD Research Department, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas, Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge","family":"Rojas-Serrano","sequence":"additional","affiliation":[{"name":"Interstitial Lung Disease and Rheumatology Unit, Instituto Nacional de Enfermedades Respiratorias Ismael Cos\u00edo Villegas, Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mayra","family":"Mej\u00eda","sequence":"additional","affiliation":[{"name":"Interstitial Lung Disease and Rheumatology Unit, Instituto Nacional de Enfermedades Respiratorias Ismael Cos\u00edo Villegas, Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rogelio","family":"P\u00e9rez-Padilla","sequence":"additional","affiliation":[{"name":"Tobacco Smoking and COPD Research Department, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas, Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Crist\u00f3bal","family":"Guadarrama-P\u00e9rez","sequence":"additional","affiliation":[{"name":"Respiratory Emergency Unit, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas, Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6877-8124","authenticated-orcid":false,"given":"Ramc\u00e9s","family":"Falf\u00e1n-Valencia","sequence":"additional","affiliation":[{"name":"HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cos\u00edo Villegas, Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,17]]},"reference":[{"key":"ref_1","unstructured":"Gene (2020, March 25). ACE2 (ENSG00000130234)\u2014Summary\u2014Homo Sapiens\u2014Ensembl Genome Browser 99. Available online: https:\/\/www.ensembl.org\/Homo_sapiens\/Gene\/Summary?db=core;g=ENSG00000130234;r=X:15561033-15602148."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1707","DOI":"10.1161\/01.CIR.0000094734.67990.99","article-title":"Increased Angiotensin-(1\u20137)-Forming Activity in Failing Human Heart Ventricles: Evidence for Upregulation of the Angiotensin-Converting Enzyme Homologue ACE2","volume":"108","author":"Zisman","year":"2003","journal-title":"Circulation"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1625","DOI":"10.3389\/fphys.2019.01625","article-title":"The Impact of Renal Denervation on the Progression of Heart Failure in a Canine Model Induced by Right Ventricular Rapid Pacing","volume":"10","author":"Chen","year":"2020","journal-title":"Front. Physiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1161\/HYPERTENSIONAHA.119.13133","article-title":"ACE2 and ADAM17 Interaction Regulates the Activity of Presympathetic Neurons","volume":"74","author":"Mukerjee","year":"2019","journal-title":"Hypertension"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"116796","DOI":"10.1016\/j.lfs.2019.116796","article-title":"Angiotensin II Type 2 Receptor and Angiotensin-Converting Enzyme 2 Mediate Ischemic Renal Injury in Diabetic and Non-Diabetic Rats","volume":"235","author":"Sharma","year":"2019","journal-title":"Life Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1007\/s11684-020-0754-0","article-title":"Single-Cell RNA-Seq Data Analysis on the Receptor ACE2 Expression Reveals the Potential Risk of Different Human Organs Vulnerable to 2019-NCoV Infection","volume":"14","author":"Zou","year":"2020","journal-title":"Front. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1021\/acschemneuro.0c00122","article-title":"Evidence of the COVID-19 Virus Targeting the CNS: Tissue Distribution, Host\u2013Virus Interaction, and Proposed Neurotropic Mechanisms","volume":"17","author":"Baig","year":"2020","journal-title":"ACS Chem. Neurosci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1007\/s00401-019-02098-6","article-title":"ACE2 Activation Protects against Cognitive Decline and Reduces Amyloid Pathology in the Tg2576 Mouse Model of Alzheimer\u2019s Disease","volume":"139","author":"Evans","year":"2020","journal-title":"Acta Neuropathol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1002\/path.1570","article-title":"Tissue Distribution of ACE2 Protein, the Functional Receptor for SARS Coronavirus. A First Step in Understanding SARS Pathogenesis","volume":"203","author":"Hamming","year":"2004","journal-title":"J. Pathol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1113\/expphysiol.2007.040246","article-title":"Distinct Roles for Angiotensin-Converting Enzyme 2 and Carboxypeptidase A in the Processing of Angiotensins within the Murine Heart","volume":"93","author":"Garabelli","year":"2008","journal-title":"Exp. Physiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.bbrc.2020.03.044","article-title":"Single Cell RNA Sequencing of 13 Human Tissues Identify Cell Types and Receptors of Human Coronaviruses","volume":"561","author":"Qi","year":"2020","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"H137","DOI":"10.1152\/ajpheart.00618.2015","article-title":"Biochemical Evaluation of the Renin-Angiotensin System: The Good, Bad, and Absolute?","volume":"310","author":"Chappell","year":"2016","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1038\/s41368-020-0074-x","article-title":"High Expression of ACE2 Receptor of 2019-NCoV on the Epithelial Cells of Oral Mucosa","volume":"12","author":"Xu","year":"2020","journal-title":"Int. J. Oral Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e105114","DOI":"10.15252\/embj.20105114","article-title":"SARS-CoV-2 Receptor ACE2 and TMPRSS2 Are Primarily Expressed in Bronchial Transient Secretory Cells","volume":"39","author":"Lukassen","year":"2020","journal-title":"EMBO J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"F670","DOI":"10.1152\/ajprenal.00451.2018","article-title":"Sex-Related Differences in the Intratubular Renin-Angiotensin System in Two-Kidney, One-Clip Hypertensive Rats","volume":"317","author":"Lee","year":"2019","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"102463","DOI":"10.1016\/j.jaut.2020.102463","article-title":"Assessing ACE2 Expression Patterns in Lung Tissues in the Pathogenesis of COVID-J","volume":"112","author":"Li","year":"2020","journal-title":"J. Autoimmun."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2829","DOI":"10.1111\/all.14429","article-title":"Distribution of ACE2, CD147, CD26, and Other SARS-CoV-2 Associated Molecules in Tissues and Immune Cells in Health and in Asthma, COPD, Obesity, Hypertension, and COVID-19 Risk Factors","volume":"75","author":"Radzikowska","year":"2020","journal-title":"Allergy"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2081","DOI":"10.1002\/jmv.25981","article-title":"Expression of the COVID-19 Receptor ACE2 in the Human Conjunctiva","volume":"92","author":"Lange","year":"2020","journal-title":"J. Med. Virol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1161\/HYPERTENSIONAHA.119.14071","article-title":"Ang II (Angiotensin II) Conversion to Angiotensin-(1\u20137) in the Circulation Is POP (Prolyloligopeptidase)-Dependent and ACE2 (Angiotensin-Converting Enzyme 2)-Independent","volume":"75","author":"Serfozo","year":"2020","journal-title":"Hypertension"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.neulet.2018.09.024","article-title":"Involvement of Angiotensin-(1\u20137) in the Neuroprotection of Captopril against Focal Cerebral Ischemia","volume":"687","author":"Tao","year":"2018","journal-title":"Neurosci. Lett."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1186\/s13046-019-1156-5","article-title":"ACE2 Inhibits Breast Cancer Angiogenesis via Suppressing the VEGFa\/VEGFR2\/ERK Pathway","volume":"38","author":"Zhang","year":"2019","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_22","first-page":"4213541","article-title":"Exosome-Mediated Transfer of ACE2 (Angiotensin-Converting Enzyme 2) from Endothelial Progenitor Cells Promotes Survival and Function of Endothelial Cell","volume":"2020","author":"Wang","year":"2020","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1159\/000430393","article-title":"Angiotensin-Converting Enzyme 2 Inhibits Apoptosis of Pulmonary Endothelial Cells during Acute Lung Injury Through Suppressing MiR-4262","volume":"37","author":"Bao","year":"2015","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.3389\/fphys.2019.01169","article-title":"Blockade of Mas Receptor or Mas-Related G-Protein Coupled Receptor Type D Reduces Portal Pressure in Cirrhotic but Not in Non-Cirrhotic Portal Hypertensive Rats","volume":"10","author":"Gunarathne","year":"2019","journal-title":"Front. Physiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4225","DOI":"10.1038\/s41598-020-61250-5","article-title":"Angiotensin-[1\u20137] Attenuates Kidney Injury in Experimental Alport Syndrome","volume":"10","author":"Choi","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1248\/bpb.b18-00985","article-title":"Effect of Prolonged Infusion of Alamandine on Cardiovascular Parameters and Cardiac ACE2 Expression in a Rat Model of Renovascular Hypertension","volume":"42","author":"Hekmat","year":"2019","journal-title":"Biol. Pharm. Bull."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.ejphar.2018.04.032","article-title":"Role of Wnt4\/\u03b2-Catenin, Ang II\/TGF\u03b2, ACE2, NF-\u03baB, and IL-18 in Attenuating Renal Ischemia\/Reperfusion-Induced Injury in Rats Treated with Vit D and Pioglitazone","volume":"831","author":"Ali","year":"2018","journal-title":"Eur. J. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e14105","DOI":"10.14814\/phy2.14105","article-title":"Both Aldosterone and Spironolactone Can Modulate the Intracellular ACE\/ANG II\/AT1 and ACE2\/ANG (1\u20137)\/MAS Receptor Axes in Human Mesangial Cells","volume":"7","author":"Stoll","year":"2019","journal-title":"Physiol. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1016\/j.bbrc.2020.02.151","article-title":"Upregulation of Angiotensin Converting Enzyme 2 by Shear Stress Reduced Inflammation and Proliferation in Vascular Endothelial Cells","volume":"525","author":"Song","year":"2020","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1538\/expanim.17-0053","article-title":"Loss of Angiotensin Converting Enzyme II (ACE2) Accelerates the Development of Liver Injury Induced by Thioacetamide","volume":"67","author":"Wu","year":"2018","journal-title":"Exp. Anim."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"523","DOI":"10.2174\/0929866526666190405123422","article-title":"Beneficial Effects of the Angiotensin-Converting Enzyme 2 Activator Dize in Renovascular Hypertension","volume":"26","author":"Kangussu","year":"2019","journal-title":"Protein Pept. Lett."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"112470","DOI":"10.1016\/j.jep.2019.112470","article-title":"Tsantan Sumtang Attenuated Chronic Hypoxia-Induced Right Ventricular Structure Remodeling and Fibrosis by Equilibrating Local ACE-AngII-AT1R\/ACE2-Ang 1\u20137-Mas Axis in Rat","volume":"250","author":"Dang","year":"2020","journal-title":"J. Ethnopharmacol."},{"key":"ref_33","first-page":"592","article-title":"Fugan Wan Alleviates Hepatic Fibrosis by Inhibiting ACE\/Ang II\/AT-1R Signaling Pathway and Enhancing ACE2\/Ang 1\u20137\/Mas Signaling Pathway in Hepatic Fibrosis Rat Models","volume":"12","author":"Li","year":"2020","journal-title":"Am. J. Transl. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1016\/j.jcmg.2019.09.005","article-title":"Plasma ACE2 Activity Predicts Mortality in Aortic Stenosis and Is Associated With Severe Myocardial Fibrosis","volume":"13","author":"Ramchand","year":"2020","journal-title":"JACC Cardiovasc. Imaging"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Wysocki, J., Schulze, A., and Batlle, D. (2019). Novel Variants of Angiotensin Converting Enzyme-2 of Shorter Molecular Size to Target the Kidney Renin Angiotensin System. Biomolecules, 9.","DOI":"10.3390\/biom9120886"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1212","DOI":"10.3389\/fphar.2019.01212","article-title":"Potassium Intake Prevents the Induction of the Renin-Angiotensin System and Increases Medullary ACE2 and COX-2 in the Kidneys of Angiotensin II-Dependent Hypertensive Rats","volume":"10","author":"Gonzalez","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"8188","DOI":"10.1007\/s12035-018-0966-3","article-title":"Stimulation of ACE2\/ANG(1\u20137)\/Mas Axis by Diminazene Ameliorates Alzheimer\u2019s Disease in the D-Galactose-Ovariectomized Rat Model: Role of PI3K\/Akt Pathway","volume":"55","author":"Kamel","year":"2018","journal-title":"Mol. Neurobiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"117388","DOI":"10.1016\/j.lfs.2020.117388","article-title":"Telmisartan\/17\u03b2-Estradiol Mitigated Cognitive Deficit in an Ovariectomized Rat Model of Alzheimer\u2019s Disease: Modulation of ACE1\/ACE2 and AT1\/AT2 Ratio","volume":"245","author":"Abdelkader","year":"2020","journal-title":"Life Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"101295","DOI":"10.1016\/j.redox.2019.101295","article-title":"Vitamin D Receptor Activation Regulates Microglia Polarization and Oxidative Stress in Spontaneously Hypertensive Rats and Angiotensin II-Exposed Microglial Cells: Role of Renin-Angiotensin System","volume":"26","author":"Cui","year":"2019","journal-title":"Redox Biol."},{"key":"ref_40","first-page":"E002","article-title":"Exploring the Mechanism of Liver Enzyme Abnormalities in Patients with Novel Coronavirus-Infected Pneumonia","volume":"28","author":"Guan","year":"2020","journal-title":"Chin. J. Hepatol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1656","DOI":"10.1002\/hep4.1434","article-title":"Liver-Targeted Angiotensin Converting Enzyme 2 Therapy Inhibits Chronic Biliary Fibrosis in Multiple Drug-Resistant Gene 2-Knockout Mice","volume":"3","author":"Rajapaksha","year":"2019","journal-title":"Hepatol. Commun."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.prostaglandins.2017.08.008","article-title":"BML-111 Equilibrated ACE-AngII-AT1R and ACE2-Ang-(1\u20137)-Mas Axis to Protect Hepatic Fibrosis in Rats","volume":"131","author":"Hu","year":"2017","journal-title":"Prostaglandins Other Lipid Mediat."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Casey, S., Schierwagen, R., Mak, K.Y., Klein, S., Uschner, F., Jansen, C., Praktiknjo, M., Meyer, C., Thomas, D., and Herath, C. (2019). Activation of the Alternate Renin-Angiotensin System Correlates with the Clinical Status in Human Cirrhosis and Corrects Post Liver Transplantation. J. Clin. Med., 8.","DOI":"10.3390\/jcm8040419"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"402","DOI":"10.4149\/neo_2019_190506N405","article-title":"Angiotensin Converting Enzymes ACE and ACE2 in Thyroid Cancer Progression","volume":"67","author":"Narayan","year":"2019","journal-title":"Neoplasma"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"113825","DOI":"10.1016\/j.bcp.2020.113825","article-title":"Downregulation of Spinal Angiotensin Converting Enzyme 2 Is Involved in Neuropathic Pain Associated with Type 2 Diabetes Mellitus in Mice","volume":"174","author":"Yamagata","year":"2020","journal-title":"Biochem. Pharmacol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1165\/rcmb.2011-0289OC","article-title":"LPS-Stimulated Cytokine Production in Type I Cells Is Modulated by the Renin-Angiotensin System","volume":"46","author":"Wong","year":"2012","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"108061","DOI":"10.1016\/j.abb.2019.07.026","article-title":"Angiotensin-Converting Enzyme 2 Regulates Autophagy in Acute Lung Injury through AMPK\/MTOR Signaling","volume":"672","author":"Zhang","year":"2019","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1159\/000443056","article-title":"ACE2 Antagonizes VEGFa to Reduce Vascular Permeability during Acute Lung Injury","volume":"38","author":"Yu","year":"2016","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"253","DOI":"10.7150\/ijbs.23489","article-title":"Instillation of Particulate Matter 2.5 Induced Acute Lung Injury and Attenuated the Injury Recovery in ACE2 Knockout Mice","volume":"14","author":"Lin","year":"2018","journal-title":"Int. J. Biol. Sci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1248\/bpb.b15-00358","article-title":"Osthole Alleviates Bleomycin-Induced Pulmonary Fibrosis via Modulating Angiotensin-Converting Enzyme 2\/Angiotensin-(1\u20137) Axis and Decreasing Inflammation Responses in Rats","volume":"39","author":"Hao","year":"2016","journal-title":"Biol. Pharm. Bull."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2387","DOI":"10.3892\/mmr.2014.3025","article-title":"Therapeutic Effect of Human Umbilical Cord Mesenchymal Stem Cells Modifed by Angiotensin-Converting Enzyme 2 Gene on Bleomycin-Induced Lung Fibrosis Injury","volume":"11","author":"Min","year":"2015","journal-title":"Mol. Med. Rep."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1007\/s11596-019-2073-8","article-title":"Dynamic Variation of RAS on Silicotic Fibrosis Pathogenesis in Rats","volume":"39","author":"Zhang","year":"2019","journal-title":"Curr. Med. Sci."},{"key":"ref_53","first-page":"419","article-title":"Protective Effect of Angiotensin (1\u20137) on Silicotic Fibrosis in Rats","volume":"32","author":"Zhang","year":"2019","journal-title":"Biomed. Environ. Sci."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1902416","DOI":"10.1183\/13993003.02416-2019","article-title":"Angiotensin Converting Enzyme 2 and Angiotensin (1\u20137) Axis in Pulmonary Arterial Hypertension","volume":"56","author":"Sandoval","year":"2020","journal-title":"Eur. Respir. J."},{"key":"ref_55","first-page":"43","article-title":"Protective Effect of Angiotensin Converting Enzyme 2 (ACE2) against Chronic Intermittent Hypoxia-Induced Pulmonary Oxidative Stress Injury in Rats","volume":"47","author":"Kou","year":"2016","journal-title":"J. Sichuan Univ. Med. Sci. Ed."},{"key":"ref_56","first-page":"4221","article-title":"Association between ACE2\/ACE Balance and Pneumocyte Apoptosis in a Porcine Model of Acute Pulmonary Thromboembolism with Cardiac Arrest","volume":"17","author":"Xiao","year":"2018","journal-title":"Mol. Med. Rep."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"7432","DOI":"10.3892\/mmr.2017.7546","article-title":"Vitamin D Alleviates Lipopolysaccharide-Induced Acute Lung Injury via Regulation of the Renin-Angiotensin System","volume":"16","author":"Xu","year":"2017","journal-title":"Mol. Med. Rep."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"L1015","DOI":"10.1152\/ajplung.00163.2018","article-title":"ACE-2\/ANG1\u20137 Ameliorates ER Stress-Induced Apoptosis in Seawater Aspiration-Induced Acute Lung Injury","volume":"315","author":"Zhang","year":"2018","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1618","DOI":"10.1111\/bph.13462","article-title":"Therapeutic Time Window for Angiotensin-(1\u20137) in Acute Lung Injury","volume":"173","author":"Kohse","year":"2016","journal-title":"Br. J. Pharmacol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"19840","DOI":"10.1038\/srep19840","article-title":"Angiotensin-Converting Enzyme 2 Inhibits Lung Injury Induced by Respiratory Syncytial Virus","volume":"6","author":"Gu","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"7027","DOI":"10.1038\/srep07027","article-title":"Angiotensin-Converting Enzyme 2 (ACE2) Mediates Influenza H7N9 Virus-Induced Acute Lung Injury","volume":"4","author":"Yang","year":"2014","journal-title":"Sci. Rep."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1198","DOI":"10.1128\/JVI.01248-09","article-title":"Differential Downregulation of ACE2 by the Spike Proteins of Severe Acute Respiratory Syndrome Coronavirus and Human Coronavirus NL","volume":"84","author":"Glowacka","year":"2010","journal-title":"J. Virol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1508","DOI":"10.1038\/nm.3985","article-title":"A SARS-like Cluster of Circulating Bat Coronaviruses Shows Potential for Human Emergence","volume":"21","author":"Menachery","year":"2015","journal-title":"Nat. Med."},{"key":"ref_64","first-page":"410","article-title":"Role of Changes in SARS-CoV-2 Spike Protein in the Interaction with the Human ACE2 Receptor: An in Silico Analysis","volume":"19","author":"Ortega","year":"2020","journal-title":"EXCLI J."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/j.micinf.2020.03.003","article-title":"Predicting the Angiotensin Converting Enzyme 2 (ACE2) Utilizing Capability as the Receptor of SARS-CoV-2","volume":"22","author":"Qiu","year":"2020","journal-title":"Microbes Infect."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1038\/s41423-020-0400-4","article-title":"Characterization of the Receptor-Binding Domain (RBD) of 2019 Novel Coronavirus: Implication for Development of RBD Protein as a Viral Attachment Inhibitor and Vaccine","volume":"17","author":"Tai","year":"2020","journal-title":"Cell. Mol. Immunol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.bbrc.2020.03.047","article-title":"Spike Protein Recognition of Mammalian ACE2 Predicts the Host Range and an Optimized ACE2 for SARS-CoV-2 Infection","volume":"526","author":"Luan","year":"2020","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Zhang, P., Leu, J.I.J., Murphy, M.E., George, D.L., and Marmorstein, R. (2014). Crystal Structure of the Stress-Inducible Human Heat Shock Protein 70 Substrate-Binding Domain in Complex with Peptide Substrate. PLoS ONE, 9.","DOI":"10.2210\/pdb4po2\/pdb"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1016\/j.cell.2020.03.045","article-title":"Structural and Functional Basis of SARS-CoV-2 Entry by Using Human ACE2","volume":"181","author":"Wang","year":"2020","journal-title":"Cell"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.cell.2020.02.058","article-title":"Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein","volume":"181","author":"Walls","year":"2020","journal-title":"Cell"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"103495","DOI":"10.1016\/j.ebiom.2021.103495","article-title":"Collateral Effects of COVID-19 Pandemic Emergency Response on Worldwide Immunizations","volume":"70","author":"Woudenberg","year":"2021","journal-title":"EBioMedicine"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2694","DOI":"10.3389\/fimmu.2020.586984","article-title":"Potential Cross-Reactive Immunity to SARS-CoV-2 From Common Human Pathogens and Vaccines","volume":"11","author":"Reche","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"e1227","DOI":"10.1002\/cti2.1227","article-title":"Identification of Similar Epitopes between Severe Acute Respiratory Syndrome Coronavirus-2 and Bacillus Calmette\u2013Gu\u00e9rin: Potential for Cross-Reactive Adaptive Immunity","volume":"9","author":"Paragi","year":"2020","journal-title":"Clin. Transl. Immunol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"2878","DOI":"10.3389\/fimmu.2020.579480","article-title":"Potential CD8+ T Cell Cross-Reactivity Against SARS-CoV-2 Conferred by Other Coronavirus Strains","volume":"11","author":"Lee","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Guo, E., and Guo, H. (2020). CD8 T Cell Epitope Generation toward the Continually Mutating SARS-CoV-2 Spike Protein in Genetically Diverse Human Population: Implications for Disease Control and Prevention. PLoS ONE, 15.","DOI":"10.1101\/2020.09.10.290841"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1038\/nm1267","article-title":"A Crucial Role of Angiotensin Converting Enzyme 2 (ACE2) in SARS Coronavirus-Induced Lung Injury","volume":"11","author":"Kuba","year":"2005","journal-title":"Nat. Med."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/j.cell.2020.02.052","article-title":"SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor","volume":"181","author":"Hoffmann","year":"2020","journal-title":"Cell"},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Guzzi, P.H., Mercatelli, D., Ceraolo, C., and Giorgi, F.M. (2020). Master Regulator Analysis of the SARS-CoV-2\/Human Interactome. J. Clin. Med., 9.","DOI":"10.1101\/2020.03.15.992925"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1410","DOI":"10.1002\/jmv.25859","article-title":"Conjunctiva Is Not a Preferred Gateway of Entry for SARS-CoV-2 to Infect Respiratory Tract","volume":"92","author":"Liu","year":"2020","journal-title":"J. Med. Virol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"6049","DOI":"10.18632\/aging.103000","article-title":"Does Comorbidity Increase the Risk of Patients with COVID-19: Evidence from Meta-Analysis","volume":"12","author":"Wang","year":"2020","journal-title":"Aging"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1002\/jmv.25785","article-title":"Organ-Protective Effect of Angiotensin-Converting Enzyme 2 and Its Effect on the Prognosis of COVID-19","volume":"92","author":"Cheng","year":"2020","journal-title":"J. Med. Virol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.ijid.2020.03.017","article-title":"Prevalence of Comorbidities and Its Effects in Patients Infected with SARS-CoV-2: A Systematic Review and Meta-Analysis","volume":"94","author":"Yang","year":"2020","journal-title":"Int. J. Infect. Dis."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1093\/ajh\/hpaa223","article-title":"SARS-CoV-2 Receptor ACE2 Gene Is Associated with Hypertension and Severity of COVID 19: Interaction with Sex, Obesity, and Smoking","volume":"34","author":"Hamet","year":"2021","journal-title":"Am. J. Hypertens."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Brake, S.J., Barnsley, K., Lu, W., McAlinden, K.D., Eapen, M.S., and Sohal, S.S. (2020). Smoking Upregulates Angiotensin-Converting Enzyme-2 Receptor: A Potential Adhesion Site for Novel Coronavirus SARS-CoV-2 (COVID-19). J. Clin. Med., 9.","DOI":"10.3390\/jcm9030841"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1915","DOI":"10.1002\/jmv.25889","article-title":"The Impact of COPD and Smoking History on the Severity of COVID-19: A Systemic Review and Meta-Analysis","volume":"92","author":"Zhao","year":"2020","journal-title":"J. Med. Virol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1002\/path.5555","article-title":"Overexpression of the SARS-CoV-2 Receptor ACE2 Is Induced by Cigarette Smoke in Bronchial and Alveolar Epithelia","volume":"253","author":"Liu","year":"2021","journal-title":"J. Pathol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1016\/j.devcel.2020.05.012","article-title":"Cigarette Smoke Exposure and Inflammatory Signaling Increase the Expression of the SARS-CoV-2 Receptor ACE2 in the Respiratory Tract","volume":"53","author":"Smith","year":"2020","journal-title":"Dev. Cell"},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Cava, C., Bertoli, G., and Castiglioni, I. (2020). In Silico Discovery of Candidate Drugs against COVID-19. Viruses, 12.","DOI":"10.3390\/v12040404"},{"key":"ref_89","first-page":"219","article-title":"Inhibitors of RAS Might Be a Good Choice for the Therapy of COVID-19 Pneumonia","volume":"43","author":"Sun","year":"2020","journal-title":"Chin. J. Tuberc. Respir. Dis."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1382","DOI":"10.1161\/HYPERTENSIONAHA.120.15082","article-title":"Renin-Angiotensin System Blockers and the COVID-19 Pandemic: At Present There Is No Evidence to Abandon Renin-Angiotensin System Blockers","volume":"75","author":"Danser","year":"2020","journal-title":"Hypertension"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1522","DOI":"10.1056\/NEJMoa2020283","article-title":"Genomewide Association Study of Severe COVID-19 with Respiratory Failure","volume":"383","author":"Ellinghaus","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1038\/s41421-020-00231-4","article-title":"Initial Whole-Genome Sequencing and Analysis of the Host Genetic Contribution to COVID-19 Severity and Susceptibility","volume":"6","author":"Wang","year":"2020","journal-title":"Cell Discov."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/s40246-021-00306-7","article-title":"Genetic Variants Are Identified to Increase Risk of COVID-19 Related Mortality from UK Biobank Data","volume":"15","author":"Hu","year":"2021","journal-title":"Hum. Genom."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1186\/s12944-018-0890-6","article-title":"Association of ACE2 Polymorphisms with Susceptibility to Essential Hypertension and Dyslipidemia in Xinjiang, China","volume":"17","author":"Pan","year":"2018","journal-title":"Lipids Health Dis."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"e026777","DOI":"10.1136\/bmjopen-2018-026777","article-title":"Genetic Associations between Genes in the Renin-Angiotensin-Aldosterone System and Renal Disease: A Systematic Review and Meta-Analysis","volume":"9","author":"Smyth","year":"2019","journal-title":"BMJ Open"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/s41421-020-0147-1","article-title":"Comparative Genetic Analysis of the Novel Coronavirus (2019-NCoV\/SARS-CoV-2) Receptor ACE2 in Different Populations","volume":"6","author":"Cao","year":"2020","journal-title":"Cell Discov."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1580","DOI":"10.1002\/jmv.25832","article-title":"Structural Variations in Human ACE2 May Influence Its Binding with SARS-CoV-2 Spike Protein","volume":"92","author":"Hussain","year":"2020","journal-title":"J. Med. Virol."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/14\/8\/805\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:45:33Z","timestamp":1760165133000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/14\/8\/805"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,17]]},"references-count":97,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2021,8]]}},"alternative-id":["ph14080805"],"URL":"https:\/\/doi.org\/10.3390\/ph14080805","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,17]]}}}