Am J Physiol Heart Circ Physiol 318: H1084–H1090, 2020.

First published March 31, 2020; doi:10.1152/ajpheart.00217.2020.

PERSPECTIVES Integrative Cardiovascular Physiology and Pathophysiology

COVID-19, ACE2, and the cardiovascular consequences

X Andrew M. South, Debra I. Diz, and X Mark C. Chappell
Cardiovascular Sciences Center, Wake Forest School of Medicine, Winston-Salem, North Carolina
Submitted 28 March 2020; accepted in final form 30 March 2020

South AM, Diz DI, Chappell MC. COVID-19, ACE2, and the apparent confusion in the literature between the ACE and
cardiovascular consequences. Am J Physiol Heart Circ Physiol 318: ACE2 components of the renin-angiotensin-aldosterone sys-
H1084 –H1090, 2020. First published March 31, 2020; doi:10.1152/ tem (RAAS), has prompted the current perspective.
ajpheart.00217.2020.—The novel SARS coronavirus SARS-CoV-2 Viral infections are dependent on cellular entry of the virus
pandemic may be particularly deleterious to patients with underlying
that uses the cellular machinery of the host to replicate multiple
cardiovascular disease (CVD). The mechanism for SARS-CoV-2
infection is the requisite binding of the virus to the membrane-bound viral copies which are subsequently shed by the host cell.
form of angiotensin-converting enzyme 2 (ACE2) and internalization Coronaviruses such as SARS-CoV-2 and SARS-CoV-1 are
of the complex by the host cell. Recognition that ACE2 is the now known to use the host protein angiotensin-converting
coreceptor for the coronavirus has prompted new therapeutic ap- enzyme-2 (ACE2, EC 3.4.17.23) as a coreceptor to gain intra-
proaches to block the enzyme or reduce its expression to prevent the cellular entry into the lungs and brain (17, 30, 52, 53, 62).
cellular entry and SARS-CoV-2 infection in tissues that express ACE2 is a membrane-bound peptidase with the majority of the
ACE2 including lung, heart, kidney, brain, and gut. ACE2, however, protein that comprises the NH2-terminal peptide domain in-
is a key enzymatic component of the renin-angiotensin-aldosterone cluding the catalytic site oriented extracellularly (3.4). ACE2 is
system (RAAS); ACE2 degrades ANG II, a peptide with multiple expressed in essentially all tissues, with greatest activity in the
actions that promote CVD, and generates Ang-(1–7), which antago- ileum and kidney followed by adipose tissue, heart, brain stem,
nizes the effects of ANG II. Moreover, experimental evidence sug-
gests that RAAS blockade by ACE inhibitors, ANG II type 1 receptor
lung, vasculature, stomach, liver, and nasal and oral mucosa
antagonists, and mineralocorticoid antagonists, as well as statins, based on activity data in the mouse that generally parallel
enhance ACE2 which, in part, contributes to the benefit of these ACE2 mRNA levels in humans (13, 53, 62), although discrep-
regimens. In lieu of the fact that many older patients with hyperten- ancies between mRNA levels and ACE2 activity or protein
sion or other CVDs are routinely treated with RAAS blockers and expression are evident (10, 11, 47). ACE2 has access to
statins, new clinical concerns have developed regarding whether these peptides in the circulation (both maternal and fetal), renal
patients are at greater risk for SARS-CoV-2 infection, whether RAAS tubular fluid, cerebrospinal fluid, interstitial fluid, and bron-
and statin therapy should be discontinued, and the potential conse- chial fluid. Consensus of evidence from various studies favors
quences of RAAS blockade to COVID-19-related pathologies such as a primary role of ACE2 to efficiently degrade ANG II to
acute and chronic respiratory disease. The current perspective criti- Ang-(1–7). ACE2 is not an aminopeptidase as recently de-
cally examines the evidence for ACE2 regulation by RAAS blockade
scribed by Zheng et al. (60) as its catalytic action that removes
and statins, the cardiovascular benefits of ACE2, and whether ACE2
blockade is a viable approach to attenuate COVID-19. the COOH-terminal phenylalanine residue of ANG II charac-
terizes ACE2 as a carboxypeptidase. This single catalytic event
ACE2; ANG II; COVID-19; renin-angiotensin system; SARS-CoV-2; reduces ANG II, the major effector of the RAAS that promotes
statins hypertension (HTN) in part by attenuating baroreceptor sensi-
tivity (BRS) for control of heart rate and promoting vasocon-
The rapid and progressive spread of the novel SARS corona- striction, sodium retention, oxidative stress, inflammation, and
virus SARS-CoV-2 pandemic that causes coronavirus-induced fibrosis, as well as increases the bioactive peptide Ang-(1–7)
disease (COVID-19) has profoundly affected the health of that opposes the ANG II-ANG II type 1 (AT1) receptor axis
thousands of individuals, strained national health care systems, through its anti-inflammatory and antifibrotic actions, as well
and significantly impacted global economic stability. The char- as enhancing BRS (Fig. 1). Thus, the ACE2 peptidase pathway
acteristics of SARS-CoV-2 that particularly distinguish this constitutes a key inflexion point in the processing pathway of
disease from influenza are a higher transmission rate combined the RAAS. Consequently, the loss of ACE2 may shift the
with a greater risk of mortality from COVID-19 primarily due system to an overall higher ANG II and lower Ang-(1–7) tone
to acute respiratory distress syndrome (ARDS) (16). While the (4, 5, 39). In contrast, ACE forms ANG II and degrades
Ang-(1–7), which produces the opposite processing of ACE2
major cause of mortality from COVID-19, particularly in older
and promotes an increase in blood pressure, inflammation, and
adults and those with compromised immune systems, is respi-
fibrosis (Fig. 1). ACE2 hydrolyzes other peptides including
ratory failure, a number of patients exhibit cardiovascular-
apelin and des-arginine bradykinin (des-Arg1-BK): apelin ex-
related pathologies including congestive heart failure (CHF)
hibits cardioprotective actions (48), while des-Arg1-BK pro-
and brain medullary cardiorespiratory dysfunction (6, 16, 32,
motes inflammation via stimulation of the B1 receptor (44).
33, 55, 60). The cardiovascular complications and the focus on
The extent that these peptides functionally contribute to the
ACE2 as the coreceptor for SARS-CoV-2, as well as the
effects of altered ACE2 activity is not well established, al-
though increased levels of des-Arg1-BK enhancing pulmonary
Correspondence: M. C. Chappell (e-mail: mchappel@wakehealth.edu). inflammation would be deleterious (44).
H1084 0363-6135/20 Copyright © 2020 the American Physiological Society http://www.ajpheart.org
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 CORONAVIRUSES AND ACE2 H1085

Angiotensinogen induced internalization would be predicted to exacerbate CVD

acutely and perhaps long term (56). ACE2 is the primary route
Renin of ANG II metabolism and Ang-(1–7) generation in the heart,
and the loss of this carboxypeptidase may compromise cardiac
ANG I function apart from or in addition to viral infection (3, 12, 24,
ACE NEP 38, 40, 43, 56). ACE2 is highly expressed in the tubular
epithelium of the kidney, and the loss of the enzyme may
ANG II Ang-(1-7) contribute to altered sodium transport leading to an increase in
AP ACE2 ACE blood volume and pressure, as well as both acute and chronic
effects on kidney injury (4, 5, 10, 22, 24, 43, 50). On the basis
ANG III Ang-(1-5) of studies on SARS-CoV and recent reports of the presence of
SARS-CoV2
ANG IV viral load in the brain stem with SARS-CoV-2, a similar
AT1R MAS-R transfer of virus to the brain by ACE2 may occur via internal-
Inflammation Anti-inflammatory
Fibrosis Anti-fibrotic ization and transport by various cranial nerves (32, 35). Cer-
Oxidative Stress Nitric Oxide tainly, neuronal cell death as a result of viral infection would
Vasoconstriction Vasorelaxation
disrupt these vital functions (32). In addition, loss of ACE2 in
Fig. 1. Processing and functional scheme of the renin-angiotensin system. The brain cardiovascular centers short of neuronal death may im-
protease renin converts the precursor angiotensinogen to angiotensin I (ANG pair proper autonomic nervous system regulation of blood
I), which is subsequently converted to ANG II by dipeptidyl carboxypeptidase
angiotensin-converting enzyme (ACE). ANG II binds to the ANG II type 1
pressure and potentially respiration (52). The loss of ACE2 in
receptor (AT1R) to stimulate inflammation, fibrosis, oxidative stress, and an the brain stem may facilitate an increase in sympathetic drive,
increase in blood pressure. ANG II is metabolized to ANG III and ANG IV alterations in the baroreflex, and exacerbation of hypertension
through various aminopeptidases (APs). ANG I and ANG II are converted to (1, 8, 54). Reduced expression of ACE2 in the vasculature may
Ang-(1–7) via endopeptidases (NEP) and the monocarboxypeptidase ACE2, also promote endothelial dysfunction and inflammation and
respectively. Ang-(1–7) binds to the Mas receptor (Mas-R) to exert anti-
inflammatory and antifibrotic actions, stimulate the release of nitric oxide, and exacerbate existing atherosclerosis and diabetes (9, 34, 42, 45,
reduce blood pressure. Ang-(1–7) is metabolized to Ang-(1–5) by ACE. Major 56, 59). A loss of pulmonary ACE2 may exacerbate hyperten-
forming and degrading pathways are depicted by solid and dashed lines, sion, respiratory distress, and fibrosis post-viral infection (20,
respectively. SARS-CoV-2 binds to ACE2 to stimulate internalization of both 30, 44). Cell surface diminution of ACE2 may contribute to
the virus and peptidase that may remove ACE2 from this pathway.
widespread inflammation observed with COVID-19. We note
that the ACE2 protein collectrin that facilitates amino acid
As to the mechanism for the intracellular entry by SARS- transport and is expressed in multiple tissues (kidney, brain,
CoV-2 and SARS-CoV, the viral coat expresses a protein vasculature, and pancreas) lacks the extracellular peptide do-
termed SPIKE (S protein) that contains a receptor-binding main of ACE2 and is not expected to directly bind and enable
region that binds to the extracellular domain of ACE2 with internalization of SARS-CoV-2 (7).
high affinity of 15 nM (50). Cleavage of the S protein along In contrast to ACE, endogenous circulating levels of soluble
dibasic arginine sites by the host protease TMPRSS2 to gen- ACE2 are generally quite low to nondetectable and would not
erate the S1 and S2 subunits is a critical step for S2-induced adequately sequester SARS-CoV-2 in the circulation to prevent
membrane fusion and viral internalization by endocytosis with viral dissemination (3). While a clinical trial on infusion of
ACE2 in the pulmonary epithelium (17, 21). The S protein is recombinant ACE2 was recently proposed and subsequently
a not a substrate for ACE2, nor does SARS-CoV-2 bind to withdrawn (NCT04287686), the extent that soluble ACE2
ACE. Wrapp and colleagues (52) suggest the greater virulence would compete for SARS-CoV-2 binding to reduce viremia
of SARS-CoV-2 may reflect that the S1 protein exhibits mark- infection and alleviate tissue injury is unknown. This approach
edly higher affinity for ACE2 as compared with that of SARS- would likely have little impact on viral infection via the
CoV. ACE2 internalization by SARS-CoV-2 would potentially respiratory system or the gut, although an increase in circulat-
result in the loss of ACE2 at the cell surface and voids a key ing ACE2 to augment the Ang-(1–7):ANG II ratio may im-
pathway for the cell to degrade ANG II and generate the prove SARS-CoV-2-induced organ injury such as ARDS and
CVD-protective Ang-(1–7). Indeed, an increase in the overall attenuate subsequent viral infection of other tissues. However,
ratio of ANG II:Ang-(1–7) following ACE2 internalization ACE2 infusion may decrease circulating ANG II and increase
may exacerbate the pulmonary tissue damage initially pro- Ang-(1–7) levels to the extent that blood pressure dysregula-
voked by SARS-CoV-2. In turn, the reduction in ACE2 may tion leading to relative hypotension could occur in patients
contribute to chronic loss of pulmonary function and increased with COVID-19 in later stages of disease including septic or
tissue fibrosis due to COVID-19. cardiogenic shock (28).
The extent to which SARS-CoV-2 infects the heart or other Experimental studies generally support the notion that
cardiovascular tissues once it enters the circulation and poten- RAAS blockade stimulates ACE2 expression and/or activity,
tially contributes to the myocarditis associated with COVID-19 although there appear to be differential responses to AT1
is unknown (16, 18, 55). In fact, the impact of SARS-CoV-2 on receptor antagonists (ARBs) versus ACE inhibitors (ACEIs),
the cardiovascular system apart from the lung is not estab- as well as tissue-dependent responses. In normotensive Lewis
lished. Cardiovascular tissues or cells that express ACE2 are and hypertensive mRen2.Lewis male rats, we found that the
potentially at risk for SARS-CoV-2 infection; however, other ARB losartan increased ACE2 activity in the heart by two- to
factors including expression of the host proteases that prime threefold as shown in Fig. 2 (11, 22); a similar increase in
the virus are required for infection as well (17, 21). In patients cardiac ACE2 activity (~2-fold) was reported for the ARB
with underlying CVD, the loss of ACE2 by SARS-CoV-2- eprosartan in rats with CHF (27). The ACEI lisinopril, how-

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H1086 CORONAVIRUSES AND ACE2

ACE2 Activity
100 Heart–Lewis 100 Heart–mRen2

80 80

fmol/mg/min
Fig. 2. Influence of angiotensin II (ANG II) 60 * * 60
type 1 receptor or angiotensin-converting en-
zyme (ACE) blockade on ACE2 activity in the
40 40
heart and kidney of normotensive Lewis and
hypertensive mRen2.Lewis rats. Chronic * *
blockade with losartan (LOS) increased car- 20 20
diac ACE2 activity by 3-fold in normotensive
Lewis and 2-fold hypertensive mRen2.Lewis
(mRen2) male rats. Lisinopril (LIS) treatment 0 0
had little or no effect on cardiac ACE2 activity CON LOS LIS CON LOS LIS
in these strains. Chronic LOS or LIS treatment
increased renal ACE2 activity in the Lewis Kidney–Lewis Kidney–mRen2
(1.3- and 1.7-fold, respectively) and mRen2 100 100
(1.3- and 1.2-fold, respectively). ACE2 activ- *
ity is the amount of Ang-(1–7) converted from * *
ANG II in the plasma membrane fraction 80 80 *
fmol/mg/min

(fmol Ang-(1–7)·mg protein⫺1·min⫺1) sensi-

tive to the ACE2 inhibitor MLN4760 (3). Data 60 60
are means ⫾ SE; n ⫽ 6 – 8. *P ⬍ 0.05 (10, 11,
22). CON, control.
40 40

20 20

0 0
CON LOS LIS CON LOS LIS

ever, either failed to increase cardiac ACE2 activity (Lewis) or protein as compared with both the control and CHF experi-
stimulated to a lesser extent than losartan (mRen2) (Fig. 2), mental groups (26). However, this raises the potential issue that
despite similar reductions in blood pressure (11, 22) Plasma while exercise is clearly associated with improved cardiovas-
and cardiac tissue contents of Ang-(1–7) paralleled the increase cular outcomes in chronic situations, exercise may contribute
in ACE2 activity following losartan treatment in the Lewis rats to a greater risk of SARS-CoV-2 infection. Keidar et al. (25)
(11). In the kidney of both strains, losartan and lisinopril reported that the mineralocorticoid antagonist spironolactone
increased ACE2 activity (10, 22), although to a lesser degree increased ACE2 activity fourfold in monocyte-derived macro-
compared with the heart (Fig. 2). Burchill et al. (2) found that phages from patients with CHF; however, spironolactone
the ACEI ramipril reduced cardiac ACE2 activity to the level failed to increase cardiac ACE2 significantly in experimental
of the control group in a rat model of acute kidney injury CHF (27). Apart from RAAS blockade, experimental studies
(AKI). Wang et al. (49) recently showed that various ARBs reveal that statins also augment the ACE2 expression. Tikoo et
(olmesartan, losartan, valsartan, candesartan, telmisartan, and al. (45) reported an increase in ACE2 protein in both heart and
irbesartan) all increased ACE2 protein to a similar extent kidney (~2-fold) of atorvastatin-treated atherosclerotic rabbits
(~2-fold) in the hearts of aorta-constricted mice. In patients that was associated with epigenetic modifications of the ACE2
with chronic kidney disease (CKD), urinary ACE2 levels (an gene. Fluvastatin treatment significantly enhanced the effects
index of renal tubular expression) in those treated with ACEIs of insulin to augment cardiac ACE2 protein expression in
or ARBs were similar to the untreated group (36). Furthermore, diabetic rats (41). To our knowledge, the influence of ARB or
Lely et al. (31) found no effect of ACEI treatment on ACE2 ACEI treatments combined with statins on ACE2 expression
protein expression in renal biopsy samples from patients with has not been established. Finally, the peroxisome proliferator-
various renal pathologies, as well as in recipients of kidney activated receptor-␥ (PPAR-␥) may influence ACE-2 expres-
transplant. In contrast, only patients treated with ACEI exhib- sion as well. The PPAR-␥ agonist rosiglitazone increased
ited an increase in intestinal ACE2 mRNA levels as compared ACE2 protein levels twofold in the aorta of hypertensive rats
with those on ARBs; however, ACE2 protein or activity were following aortic coarctation (39). Oudit and colleagues (61)
not assessed to validate the mRNA results (46). found that telmisartan, a partial PPAR-␥ agonist, also increased
In the brain stem of older rats, losartan treatment increased ACE2 protein expression in aorta which was associated with
ACE2 mRNA levels twofold; ACE2 was the primary peptidase greater PPAR-␥ content in the spontaneously hypertensive rat.
to generate Ang-(1–7) in this brain region (8, 14). Chronic The extent that ARBs with PPAR-␥ agonistic actions such as
exercise may be another important stimulus of ACE2 in the telmisartan and irbesartan exhibit a greater effect on ACE2
brain and the periphery (37). In the rostral ventrolateral me- expression in different tissues is unknown, although Wang et
dulla (RVLM), an exercise regimen markedly increased ACE2 al. (49) found no difference in the increase in cardiac ACE2

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 CORONAVIRUSES AND ACE2 H1087
among six different ARBs that included both telmisartan and nM [5,000 pg/ml] that increased up to 20 nM [20,000 pg/ml] in
irebesartan. patients with the influenza A H7N9N1 virus that far exceeds
The influence of RAAS blockade on pulmonary ACE2 has accepted plasma ANG II concentrations (19). This latter study
not been evaluated thoroughly, but ACEI and ARB treatment underscores that appropriate methods to accurately quantify
may improve outcomes in patients with ARDS (27). In exper- ANG II, ACE2, and other RAAS component are vital to
imental studies, Yuan et al. (57) reported reduced ACE2 establish the role of the RAAS in patients with COVID-19.
protein in the lungs of rats subjected to chronic smoking and Biochemical approaches to assess the peptide and protein
that losartan treatment was beneficial but failed to increase components of the RAAS in plasma and tissues, as well as the
ACE2 in either the control or the smoking-exposed groups. expected endogenous peptide values, were recently reviewed
However, there are inconsistencies in the stated conclusions of by Chappell (3). The study of Liu et al. (33) also failed to
this study that are not supported by the data, as well as the include blood pressure data for each patient which could
extremely high ANG II content reported in the lung tissue substantiate the higher circulating levels of ANG II. Patients
(⬎10 ␮g/mg or 10 nmol/mg protein) whereby ANG II would with more severe COVID-19 are reported to have hypokalemia
comprise 1% of the total protein content in lung (57). In a and higher blood pressure as compared with those with milder
model of LPS-induced ARDS, losartan improved pulmonary COVID-19 that would support a role for a stimulated ANG
function and inflammation (51). Losartan treatment was asso- II-AT1 receptor axis (6). Current clinical data on the ACE2-
ciated with higher ACE2 activity in bronchoalveolar lavage Ang-(1–7) pathway, however, are quite limited relative to the
fluid (BALF) compared with that of the ARB-treated controls; experimental data, especially in regard to the effects of ACEI
losartan reduced ACE2 activity by 50% in the ventilated and ARB. Furthermore, the existing evidence, though novel
control group (49). Changes in ANG II and Ang-(1–7) BALF and insightful, often comes from smaller cross-sectional ob-
content evaluated by HPLC-mass spectroscopy paralleled al- servational studies with incomplete RAAS measurements that
terations in ACE2 activity (51). We are not aware of studies in cannot fully account for potential sources of bias and con-
animals or humans that have examined the effects of ACEI on founding.
pulmonary ACE2, and the discrepancy between ARBs and There are essentially no clinical data on how ACEIs or
ACEIs to augment ACE2 activity clearly requires further ARBs may impact the ACE2-Ang-(1–7) pathway in lung, heart
evaluation. The effect of ARBs or ACEIs on the expression of or brain. Thus, additional data are urgently needed on the
the SPIKE proteases on the host cell that facilitate binding and effects of ACEI and ARB on human pulmonary disease and
entry of SARS-CoV-2 is also unknown. ARBs substantially RAAS expression, particularly the response of the ACE2-Ang-
increase the circulating levels of ANG II arising from the (1–7)-Mas receptor axis. Ang-(1–7) itself may potentially
disinhibition of kidney renin release, and whether the higher serve as a novel therapeutic to treat COVID-19. In both LPS-
ANG II levels compete for SARS-CoV-2 binding to ACE2 is and acid-induced ARDS with high-stretch ventilation, Ang-
unclear. In collaborative studies with the McCray laboratory, (1–7) infusion improved oxygenation, reduced the acute in-
we reported that the SPIKE protein from SARS-CoV did not flammatory response, and reduced subsequent tissue fibrosis
attenuate hydrolysis of ANG II to Ang-(1–7) by soluble ACE2, (51, 58). Clinical trials are in development to test the effects of
thus it may be unlikely that ANG II or other peptide substrates the ARB losartan in patients with COVID-19 (NCT04311177
would directly interfere with SAR-CoV-2 binding and inter- and NCT04312009). Upregulation of the ACE2-Ang-(1–7)
nalization (23). pathway of the RAAS is well known to counter-regulate the
Finally, our knowledge of the cardiovascular consequences proinflammatory and profibrotic effects of the ACE-ANG II-
of SARS-CoV-2 infection in patients at this early point is quite AT1 receptor axis in experimental models of HTN and CVD
limited. Liu et al. (33) recently reported that the circulating (4, 5, 24, 40). Indeed, experimental studies demonstrate that
levels of ANG II were significantly higher in patients with the ACE2-Ang-(1–7) pathway mediates some of the beneficial
COVID-19 than those of healthy controls that would be con- effects of ACEI and ARB in these diseases including improved
sistent with lower ACE2 activity. Moreover, plasma ANG II regulation of autonomic control of blood pressure (3, 5, 40,
content significantly correlated with both the viral load in 56), though data in humans remains limited. Experimental
BALF and pulmonary function in the SARS-CoV-2 cohort evidence to date strongly suggests that ANG II may promote
(33). Thus, as suggested by Liu and colleagues, whether a acute lung injury and ARDS induced by coronaviruses, includ-
direct ANG II ACE2 interaction occurs or changes in pulmo- ing SARS-CoV, SARS-CoV-2/COVID-19, and possibly in
nary or cardiac function in these patients alters RAAS expres- MERS-CoV (20, 30, 51).
sion cannot be ascertained. However, this clinical study com- We emphasize that further investigation into these potential
prised only 12 patients, and circulating ACE2 or ACE levels mechanisms is urgently required, now given the complex
were not determined. Moreover, an increase in circulating interplay of the RAAS and novel coronaviruses such as SARS-
ANG II may reflect changes in a number of RAAS components CoV-2. Particularly relevant information includes the status of
as opposed to solely a reduction in ACE2 activity (Fig. 1). the RAAS at baseline, during and after the infection and during
Plasma ANG II levels in the study of Liu et al. (33) ranged progression of COVID-19 and following recovery. Compre-
from 100 pM in healthy controls to 500 pM in the SARS- hensive assessments of the full complement of RAAS compo-
CoV-2 cohort [100 –500 pg/ml] using an ELISA-based method nents across this timeline particularly in concert with medical
in which the patient plasma was directly assayed; these values management of the patient during different phases of the
are 5–10-fold higher than expected ANG II levels in plasma disease are required to establish whether the ACE-ANG II-
but are in an acceptable range particularly if the patients were AT1 receptor versus ACE2-Ang-(1–7)-Mas receptor pathways
ventilated (3). In contrast, their previous study using a different are beneficial or detrimental at a given point in time. This
ELISA reported plasma ANG II values in control subjects of 5 situation is not surprising since the RAAS has both an imme-

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H1088 CORONAVIRUSES AND ACE2

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This work was supported by National Institutes of Health Grants HL- 14. Gilliam-Davis S, Gallagher PE, Payne VS, Kasper SO, Tommasi EN,
146818, HL-05952, HD-084227, and HL-56973; American Heart Association Westwood BM, Robbins ME, Chappell MC, Diz DI. Long-term sys-
Grants AHA-151521 and AHA-18TPA34170522; and Cardiovascular Sci- temic angiotensin II type 1 receptor blockade regulates mRNA expression
ences Center Grant CVSC-830114 and by the Hypertension and Vascular of dorsomedial medulla renin-angiotensin system components. Physiol
Research Center and the Farley Hudson Foundation. Genomics 43: 829 –835, 2011. doi:10.1152/physiolgenomics.00167.2010.
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DISCLOSURES
marker of tissue perfusion and prognosis in critically ill patients. Crit Care
No conflicts of interest are declared by the authors. Med 47: 152–158, 2019. doi:10.1097/CCM.0000000000003544.
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AUTHOR CONTRIBUTIONS Lei CL, Hui DSC, Du B, Li LJ, Zeng G, Yuen KY, Chen RC, Tang
CL, Wang T, Chen PY, Xiang J, Li SY, Wang JL, Liang ZJ, Peng YX,
M.C.C. conceived and designed research; M.C.C. performed experiments; Wei L, Liu Y, Hu YH, Peng P, Wang JM, Liu JY, Chen Z, Li G,
M.C.C. analyzed data; M.C.C. interpreted results of experiments; M.C.C. Zheng ZJ, Qiu SQ, Luo J, Ye CJ, Zhu SY, Zhong NS; China Medical
prepared figures; A.M.S., D.D., and M.C.C. drafted manuscript; A.M.S., D.D., Treatment Expert Group for Covid-19. Clinical characteristics of 183
and M.C.C. edited and revised manuscript; A.M.S., D.D., and M.C.C. ap- coronavirus disease 2019 in China. N Engl J Med. 2020 Feb 28 [Epub
proved final version of manuscript. ahead of print]. doi:10.1056/NEJMoa2002032.
17. Hoffmann M, Kleine-Wever H, Kruger N, Muller M, Drotsten C,
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