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The pivotal link between ACE2 deficiency and SARS-CoV-2 infection.
Eur J Intern Med. 2020 06; 76:14-20.EJ

Abstract

Angiotensin converting enzyme-2 (ACE2) receptors mediate the entry into the cell of three strains of coronavirus: SARS-CoV, NL63 and SARS-CoV-2. ACE2 receptors are ubiquitous and widely expressed in the heart, vessels, gut, lung (particularly in type 2 pneumocytes and macrophages), kidney, testis and brain. ACE2 is mostly bound to cell membranes and only scarcely present in the circulation in a soluble form. An important salutary function of membrane-bound and soluble ACE2 is the degradation of angiotensin II to angiotensin1-7. Consequently, ACE2 receptors limit several detrimental effects resulting from binding of angiotensin II to AT1 receptors, which include vasoconstriction, enhanced inflammation and thrombosis. The increased generation of angiotensin1-7 also triggers counter-regulatory protective effects through binding to G-protein coupled Mas receptors. Unfortunately, the entry of SARS-CoV2 into the cells through membrane fusion markedly down-regulates ACE2 receptors, with loss of the catalytic effect of these receptors at the external site of the membrane. Increased pulmonary inflammation and coagulation have been reported as unwanted effects of enhanced and unopposed angiotensin II effects via the ACE→Angiotensin II→AT1 receptor axis. Clinical reports of patients infected with SARS-CoV-2 show that several features associated with infection and severity of the disease (i.e., older age, hypertension, diabetes, cardiovascular disease) share a variable degree of ACE2 deficiency. We suggest that ACE2 down-regulation induced by viral invasion may be especially detrimental in people with baseline ACE2 deficiency associated with the above conditions. The additional ACE2 deficiency after viral invasion might amplify the dysregulation between the 'adverse' ACE→Angiotensin II→AT1 receptor axis and the 'protective' ACE2→Angiotensin1-7→Mas receptor axis. In the lungs, such dysregulation would favor the progression of inflammatory and thrombotic processes triggered by local angiotensin II hyperactivity unopposed by angiotensin1-7. In this setting, recombinant ACE2, angiotensin1-7 and angiotensin II type 1 receptor blockers could be promising therapeutic approaches in patients with SARS-CoV-2 infection.

Authors+Show Affiliations

Fondazione Umbra Cuore e Ipertensione-ONLUS and Struttura Complessa di Cardiologia, Ospedale S. Maria della Misericordia, Perugia.. Electronic address: verdecchiapaolo@gmail.com.Fondazione Umbra Cuore e Ipertensione-ONLUS and Struttura Complessa di Cardiologia, Ospedale S. Maria della Misericordia, Perugia.Dipartimento di Medicina e Chirurgia, Università degli Studi dell'Insubria, Varese; Dipartimento di Medicina e Riabilitazione Cardio-Respiratoria, Istituti Clinici Scientici Maugeri, IRCCS Tradate (VA).Dipartimento di Medicina e Chirurgia, Università degli Studi dell'Insubria, Varese; Dipartimento di Medicina e Riabilitazione Cardio-Respiratoria, Istituti Clinici Scientici Maugeri, IRCCS Tradate (VA).

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

32336612

Citation

Verdecchia, Paolo, et al. "The Pivotal Link Between ACE2 Deficiency and SARS-CoV-2 Infection." European Journal of Internal Medicine, vol. 76, 2020, pp. 14-20.
Verdecchia P, Cavallini C, Spanevello A, et al. The pivotal link between ACE2 deficiency and SARS-CoV-2 infection. Eur J Intern Med. 2020;76:14-20.
Verdecchia, P., Cavallini, C., Spanevello, A., & Angeli, F. (2020). The pivotal link between ACE2 deficiency and SARS-CoV-2 infection. European Journal of Internal Medicine, 76, 14-20. https://doi.org/10.1016/j.ejim.2020.04.037
Verdecchia P, et al. The Pivotal Link Between ACE2 Deficiency and SARS-CoV-2 Infection. Eur J Intern Med. 2020;76:14-20. PubMed PMID: 32336612.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The pivotal link between ACE2 deficiency and SARS-CoV-2 infection. AU - Verdecchia,Paolo, AU - Cavallini,Claudio, AU - Spanevello,Antonio, AU - Angeli,Fabio, Y1 - 2020/04/20/ PY - 2020/04/13/received PY - 2020/04/16/accepted PY - 2020/4/28/pubmed PY - 2020/6/19/medline PY - 2020/4/28/entrez KW - ACE KW - ACE-inhibitors KW - ACE2 KW - Angiotensin receptor blockers KW - Coronavirus KW - Diabetes KW - Elderly KW - Heart failure KW - Hypertension KW - SARS-CoV-2 SP - 14 EP - 20 JF - European journal of internal medicine JO - Eur J Intern Med VL - 76 N2 - Angiotensin converting enzyme-2 (ACE2) receptors mediate the entry into the cell of three strains of coronavirus: SARS-CoV, NL63 and SARS-CoV-2. ACE2 receptors are ubiquitous and widely expressed in the heart, vessels, gut, lung (particularly in type 2 pneumocytes and macrophages), kidney, testis and brain. ACE2 is mostly bound to cell membranes and only scarcely present in the circulation in a soluble form. An important salutary function of membrane-bound and soluble ACE2 is the degradation of angiotensin II to angiotensin1-7. Consequently, ACE2 receptors limit several detrimental effects resulting from binding of angiotensin II to AT1 receptors, which include vasoconstriction, enhanced inflammation and thrombosis. The increased generation of angiotensin1-7 also triggers counter-regulatory protective effects through binding to G-protein coupled Mas receptors. Unfortunately, the entry of SARS-CoV2 into the cells through membrane fusion markedly down-regulates ACE2 receptors, with loss of the catalytic effect of these receptors at the external site of the membrane. Increased pulmonary inflammation and coagulation have been reported as unwanted effects of enhanced and unopposed angiotensin II effects via the ACE→Angiotensin II→AT1 receptor axis. Clinical reports of patients infected with SARS-CoV-2 show that several features associated with infection and severity of the disease (i.e., older age, hypertension, diabetes, cardiovascular disease) share a variable degree of ACE2 deficiency. We suggest that ACE2 down-regulation induced by viral invasion may be especially detrimental in people with baseline ACE2 deficiency associated with the above conditions. The additional ACE2 deficiency after viral invasion might amplify the dysregulation between the 'adverse' ACE→Angiotensin II→AT1 receptor axis and the 'protective' ACE2→Angiotensin1-7→Mas receptor axis. In the lungs, such dysregulation would favor the progression of inflammatory and thrombotic processes triggered by local angiotensin II hyperactivity unopposed by angiotensin1-7. In this setting, recombinant ACE2, angiotensin1-7 and angiotensin II type 1 receptor blockers could be promising therapeutic approaches in patients with SARS-CoV-2 infection. SN - 1879-0828 UR - https://www.unboundmedicine.com/medline/citation/32336612/The_pivotal_link_between_ACE2_deficiency_and_SARS_CoV_2_infection_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0953-6205(20)30151-5 DB - PRIME DP - Unbound Medicine ER -