key: cord-262000-k32cb9ym authors: Li, Xue-Ting; Liu, Ying; Song, Juan-Juan; Zhong, Jiu-Chang title: Letter to the Editor: Increased plasma ACE2 concentration does not mean increased risk of SARS-CoV-2 infection and increased fatality rate of COVID-19 date: 2020-09-07 journal: Acta Pharm Sin B DOI: 10.1016/j.apsb.2020.09.003 sha: doc_id: 262000 cord_uid: k32cb9ym nan Short title: ACE2, SARS-CoV-2 and COVID-19 To the Editor: More recently, the ongoing dissemination of the novel coronavirus disease 2019 (COVID-19) is posing an unprecedented threat to global healthcare systems 1, 2 . Since the outbreak, COVID-19 has escalated to well over 24,775,000 cases and caused over 837,000 deaths worldwide by August 29, 2020. Angiotensin converting enzyme 2 (ACE2) has garnered widespread interest as the receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative virus of COVID-19 pandemic, providing a critical link among COVID-19, inflammatory storm, ACE2 and cardiovascular disease 1,2 . Thus, this brings controversy and challenge to clinical practice: does increased ACE2 level mean increased risk of SARS-CoV-2 infection and increased fatality rate of COVID-19? The latest view from Sama et al. 1 was that higher plasma ACE2 concentrations in patients with heart failure might explain for the higher incidence and fatality rate of COVID-19 in men 1 . They demonstrated that the strongest predictor of elevated concentrations of ACE2 was male sex in both cohorts, and use of ACE inhibitors (ACEI) or angiotensin (Ang) receptor blockers (ARB) was not an independent predictor of plasma ACE2 in the index cohort while ACEI and ARB use were independent predictors of lower plasma ACE2 in the validation cohort 1 . Therefore, they concluded that higher plasma ACE2 might explain the higher incidence and fatality of COVID-19 in men, and ACEI or ARB could not increase the vulnerability for the COVID-19 through increased plasma ACE2 concentrations. Here, we put forward a completely different perspective on the causal relationship between ACE2 and SARS-CoV-2 infection and aggravation of COVID-19. Firstly, we think that the conclusions drawn from the results of the two cohorts in this article are one-sided viewpoint in some respects, likely contributing to the unreasonable speculation. Previous research evidence indicates that increased ACE2 levels in lung tissues are associated with the vulnerability of SARS-CoV-2, and ACE2 is proved to be highly expressed in secretory cells in the lung epithelium 3 , the wide surface of alveolar epithelial cells might explain for the vulnerability of this organ to SARS-CoV-2 invasion. However, it is inappropriate to speculate a higher tissue expression of ACE2 according to a higher plasma ACE2 concentration since ACE2 is mainly a membrane-anchored enzyme. The view from Sama et al. 1 was that male sex was the strongest predictor of elevated concentrations of circulating ACE2, while Smith et al. 3 demonstrated that ACE2 levels in mammalian lungs did not vary by age or sex. This discrepancy reflected the inconsistency between circulating ACE2 and tissue ACE2 laterally. Furthermore, it is of great significance to distinguish the concepts of different forms of ACE2 and explore the potential J o u r n a l P r e -p r o o f relations within them. The membrane-bound ACE2 (mACE2) serves as the major SARS-CoV-2 receptor via attaching to the viral Spike protein thus directly mediates the endocytosis of the virus 2 . Soluble ACE2 (sACE2) is produced by the hydrolysis and shedding from mACE2, small amounts of the sACE2 normally exists in circulating blood 4 . Both the mACE2 and sACE2 could catalyze Ang II conversion to protective peptide Ang-(1-7) which, by virtue of its actions on the Mas receptor, opposes the molecular and cellular effects of Ang II 2,5 . Remarkably, recombinant human ACE2 (rhACE2), sACE2, ACE2-Fc, and ACE2-Ig are thought to be promising therapeutic approaches for COVID-19 patients with SARS-CoV-2 infection through competitive inhibiting the binding of viral Spike protein to mACE2 4 . Secondly, there is currently no conclusive evidence that increased ACE2 level will lead to increased susceptibility for SARS-CoV-2 infection and aggravation of COVID-19. It is reported that ACE2 expression is higher in kidney and ileum than in lung, but both kidney and ileum are not at higher risk of SARS-CoV-2 infection than that of lung, indicating other complicated mechanisms might be involved in the vulnerability of SARS-CoV-2 and COVID-19 2,6,7 . Zou et al. 8 identified the organs with high and low vulnerability according to ACE2 expression and constructed a risk map indicating the vulnerability of different organs to COVID-19 infection inconsistent with the distribution of ACE2. In addition to ACE2 receptor, a disintegrin and metallopeptidase domain 17 (ADAM17), transmembrane protease serine 2 (TMPRSS2), and host molecules such as CD147, GRP78, furin, cathepsin B and cathepsin L may mediate the viral binding and entry processes of SARS-CoV-2 infection ( Fig. 1) 2, 6 . Notably, a circulating sACE2 ectodomain can be shed following proteolytic cleavage by ADAM17 resulting in loss of ACE2 from the cell surface while TMPRSS2 could activate spike protein of SARS-CoV-2 and cleave the C-terminal segment of ACE2 (Fig. 1) , thus enhancing the ability of virus spike protein to enter host cells 2,6 . Furthermore, increased ACE2 could bind to amino acid transporter B°AT1 and overlay the sites where ACE2 is cleaved by TMPRSS2 (Fig. 1) 2 . The expression level of B°AT1 in lung tissue is lower than that in intestine and kidney, which may be one of the reasons why SARS-CoV-2 is prone to infect the lung rather than the intestine and kidney 2 . ACE2 binding virus requires various co-factors, co-receptors and related signal molecules in the complicated infective process of SARS-CoV-2. Thus, increased plasma ACE2 does not completely reflect increased risk of SARS-CoV-2 infection. Thirdly, the major contributor to progressively worsened systemic manifestations of COVID-19 was due to an imbalance of the Ang-(1-7)/Ang II through a loss of functional tissue ACE2 instead of elevated ACE2 level, thus leading to severe inflammatory storm 2 . Intriguingly, circulating Ang II level was obviously elevated in COVID-19 patients with lung injury (Table 1) 9 which further upregulates ADAM-17 activity by interacting with AT1 receptors, leading to more shedding of ACE2 and thereby accelerating renin-angiotensin-aldosterone system (RAAS)-mediated injury including severe cardiopulmonary damage (Fig. 1) (Table 1) 10 . Among hospitalized patients with COVID-19 and coexisting hypertension, inpatient use of ACEI/ARB was associated with lower risk of all-cause mortality compared with ACEI/ARB nonusers (Table 1) 11 . Patients with heart failure have elevated plasma ACE2 level due to increased shedding of tissue ACE2, which may predispose them to the RAAS imbalance mediated by SARS-CoV-2 that further depletes ACE2-mediated protection in heart and lung 2 . Increased sACE2 activity in patients with heart failure indicates an overactive cardioprotective arm of the RAAS to counteract detrimental effects of Ang II 2 . Importantly, in pre-clinical models and clinical populations ( Table 1) , use of rhACE2 in patients with hypertension, heart failure and acute lung injury led to a prompt increase in the Ang (1-7)/Ang II ratio and improvement of pathological hypertrophy, cardiopulmonary fibrosis, inflammation, oxidant injury and heart dysfunction, also reflecting ACE2-mediated cardiopulmonary protective impacts 2, [12] [13] [14] [15] [16] [17] [18] [19] . Furthermore, clinical grade recombinant human sACE2 reduced SARS-CoV-2 recovery from Vero cells, human blood vessel organoids and human kidney organoids, implying that sACE2 can significantly block early stages of SARS-CoV-2 infections 20 . Besides of Ang II, ACE2 also could hydrolyze apelin-13 to apelin-12 which binds to APJ receptor and mediates cardiovascular protective effects such as vasodilation and positive inotropic action ( Fig. 1) 21 . Apelin and its receptor APJ agonists are of great potential treatment for COVID-19 through blockade of the RAAS and upregulation of ACE2, which is a key mechanism to inhibit excessive ACE and the Ang II-AT1 signaling activation 22, 23 . Exogenous apelin/ACE2 signaling could improve lung injury and alleviate cardiovascular complications through enhancing Ang(1-7)/Ang-II ratio (Fig. 1) [21] [22] [23] . Collectively, ACE2 has trivalent function: a receptor for SARS-CoV-2, a negative regulator of the RAAS and a partner for amino acid transporters B°AT1. Increased ACE2 concentration does not mean increased risk of SARS-CoV-2 infection and increased cardiovascular comorbidities in men with greater incidence and fatality rate of COVID-19. Notably, rhACE2, sACE2, ACE2-Fc, ACE2-Ig and Apelin are currently being considered as potential therapeutic options in treatment of COVID-19. 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