key: cord-1055519-ybr2ij5b authors: Manuel González-Rayas, José; Rayas-Gómez, Ana Lilia; Juan García-González, José; Manuel González-Yáñez, José; Ascención Hernández-Hernández, José; López-Sánchez, Rosa del Carmen title: COVID-19, ACE -inhibitors and angiotensin receptor blockers-: The need to differentiate between early infection and acute lung injury date: 2020-04-22 journal: nan DOI: 10.1016/j.rccar.2020.04.005 sha: 025694dc05686319c2b00e46947ef8d00d4ac769 doc_id: 1055519 cord_uid: ybr2ij5b nan J o u r n a l P r e -p r o o f distributed globally and has become the focus of extensive medical research, as the number of cases keeps rising. A significant part of the investigative effort has been directed to the search for an effective therapy or intervention that could stop the spread of the disease or be used to effectively treat infected patients. Likewise, potential predisposing factors to develop a more severe clinical presentation are progressively being identified. Some of the more relevant are older age and the presence of certain comorbidities, such as cerebrovascular and coronary heart disease, hypertension and diabetes [5] [6] [7] [8] . It is important to highlight that the last two are chronic conditions commonly treated with ACE-inhibitors and angiotensin II type-I receptor blockers [9] [10] [11] . However, the evidence suggests that these medications can upregulate the expression of angiotensin converting enzyme 2 (ACE2), the cellular receptor for both SARS-CoV and SARS-CoV-2 [11] [12] [13] [14] [15] [16] . Thus, a group of researchers hypothesized that ACE2increasing drugs could raise the risk of infection and prompt a more severe clinical course or a fatal outcome in diabetic and hypertensive patients 11 . As a result, the safety of ACE-inhibitors and angiotensin receptor blockers in COVID-19 patients was put into question and an intense debate arose. Nonetheless, although the idea of the intensification of ACE2 receptor expression, leading to an increased risk of COVID-19 infection is reasonable, hypertension and diabetes are also frequent comorbidities of MERS-CoV 17 . The latter is relevant since MERS-CoV uses a distinct host-cell receptor, namely the dipeptidyl peptidase 4 (DPP4), also known as CD26. Hence, it would seem that the relation between chronic conditions and SARS-CoV-2 could be explained by the general Furthermore, we suggest that SARS-CoV-2 infection should not just be considered as a single but as a dual phase phenomenon. Therefore, in the first phase of SARS-CoV-2 infection, expressing a higher number of ACE2 receptors could indeed promote viral entry 11 . However, in a second or a later phase of the infection, ACE2 receptors may be protective of SARS-CoV-2 mediated acute lung injury 18, 19 . In fact, experimental evidence shows that SARS-CoV infection is paired with a decrease in the expression of ACE2 [18] [19] [20] . As a consequence, the physiological antagonism of ACE2 over the classical renin-angiotensin-aldosterone system (RAAS) is blunted. In normal circumstances, the vasoconstrictor peptide angiotensin II is metabolized by ACE2 to produce angiotensin 1-7 (Ang 1-7) 18 . Ang 1-7 is then able to interact with Mas, a G-protein-coupled receptor with known vasoprotective effects 18, 19, 21, 22 . Moreover, Ang 1-7 has been shown to reduce inflammation, tissue damage and lung edema in the set of acute respiratory distress syndrome 23 . This suggests that along with the viral load and the host immune response to SARS-CoV-2, an over-active RAAS could contribute to the exacerbated lung injury generated by COVID-19. Thus, recombinant ACE2 may be an effective therapeutic approach to treat COVID-19 cases, as some studies already suggest 24 . Additionally, cyclic Ang 1-7, which shows increased resistance to human peptidases, such as angiotensin-converting enzyme (ACE) and dipeptidyl peptidase 3 (DPP3), could counteract the downregulation of ACE2 caused by SARS-CoV-2 infection 25, 26 . Finally, it is important to mention that the protease (Ang 1-7 generation) and the SARS-CoV receptor functions of ACE2 are independent 18 . In consequence, catalytically inactive ACE2 receptors can still interact with viral particles. Moreover, ACE2 is still active while the SARS spike proteins is bound 18, 27 . This is important, since it opens the possibility for the development of selective drugs that specifically target the ACE2 domain used by the SARS-CoV-2 to enter the host-cell without affecting the production of Ang 1-7. Nonetheless, intensive experimental and clinical research should validate the feasibility of this approach. The authors report no conflicts of interest. None. None. 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