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The ACE2 expression in human heart indicates new potential mechanism of heart injury among patients infected with SARS-CoV-2
Open accessAbstract
A new type of pneumonia caused by a novel coronavirus SARS-CoV-2 outbreaks recently in China and spreads into many other countries. This disease, named as COVID-19, is similar to patients infected by SARS-CoV and MERS-CoV, and nearly 20% of patients developed severe condition. Cardiac injury is a prevalent complication of severe patients, exacerbating the disease severity in coronavirus disease 2019 (COVID-19) patients. Angiotensin-converting enzyme 2 (ACE2), the key host cellular receptor of SARS-CoV-2, has been identified in multiple organs, but its cellular distribution in human heart is not illuminated clearly. This study performed the first state-of-art single cell atlas of adult human heart, and revealed that pericytes with high expression of ACE2 might act as the target cardiac cell of SARS-CoV-2. The pericytes injury due to virus infection may result in capillary endothelial cells dysfunction, inducing microvascular dysfunction. And patients with basic heart failure disease showed increased ACE2 expression at both mRNA and protein levels, meaning that if infected by the virus these patients may have higher risk of heart attack and critically ill condition. The finding of this study explains the high rate of severe cases among COVID-19 patients with basic cardiovascular disease; and these results also perhaps provide important reference to clinical treatment of cardiac injury among severe patients infected by SARS-CoV-2.
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“ACE2, TMPRSS2, NRP1, integrins, and cathepsins are also expressed on mast cells (Figure 1), 28,29”
From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [29]
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ResultMyocardial Angiotensin Metabolism in End-Stage Heart Failure
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“However, ACE2 expression has also been observed in enterocytes of the small intestine, pericytes of the heart, and endothelial cells in various organs, including the brain (19, 20).”
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“ACE2 is widely expressed in cardiac myocytes, vascular smooth muscle cells (VSMCs), and vascular endothelial cells (Patel et al., 2014; Chen et al., 2020; Evans et al., 2020; Nicin et al., 2020).”
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“Pericytes—the mural cells lining microvasculature, interacting with endothelial cells notably to maintain microvascular stability—exhibited the strongest ACE2 expression in HF patients [185], rendering these cells involved in the coronary vasculature of the myocardium, more susceptible to infection.”
BackgroundCanatan, D., Corrons, J. L. V. I., & Sanctis, V. D. (2020) · PubMed Central · doi:10.23750/abm.v91i4.10665 · Cited by 27
“to be increased in COVID-19 patients compared to healthy adults (7-9).”
BackgroundCurrent targets and drug candidates for prevention and treatment of SARS-CoV-2 (COVID-19) infection
Goyal, R. K., Majeed, J., Tonk, R. K., Dhobi, M., Patel, B. M., Sharma, K., & Apparsundaram, S. (2020) · Reviews in Cardiovascular Medicine · doi:10.31083/j.rcm.2020.03.118 · Cited by 28
“is also present in the oral and nasal mucosa, skin, lymph nodes, thymus, bone marrow, spleen, liver, and brain (Bilinska et al., 2020; Chen et al., 2020; Hamming et al., 2004; Li et al., 2020a; Zhang et al., 2020), regulating the vasculature, inflammation, oxidative stress, fibrosis, and cell proliferation.”
BackgroundCardiovascular protective properties of oxytocin against COVID-19
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“Patients with heart failure show increased ACE2 expression at both mRNA and protein levels [35].”
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Risk Factors for Myocardial Injury in Patients with Coronavirus Disease 2019 in China
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“It has been shown that both SARS‐CoV and SARS‐CoV‐2 use angiotensin‐converting enzyme 2 (ACE2), which is highly expressed in the heart and vasculature, as a cell entry receptor.(22,23) Previous studies indicated that SARS‐CoV is detectable and ACE2 expression is down‐regulated in the heart of infected patients, leadin…”
MethodAngiotensin-converting enzyme 2, coronavirus disease 2019, and abdominal aortic aneurysms
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“However, other investigations have assumed the primary role in the involvement of microvascular pericytes, as these types of cells express high levels of the ACE2 receptor [90,94,95].”
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“Pericytes have been reported to express ACE-2 making them a potential target for infection by SARS-CoV-2 [56].”
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“ACE-2 are the key receptors involved in the priming of spike glycoprotein of virions and are expressed mostly in the pericytes of heart than the lungs (Chen et al., 2020).”
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Gilbert, R. E., Caldwell, L., Misra, P. S., Chan, K., Burns, K. D., Wrana, J. L., & Yuen, D. A. (2020) · Canadian Journal of Diabetes · doi:10.1016/j.jcjd.2020.07.003 · Cited by 25
“Indeed, macrophages and pericytes have been shown to express high levels of ACE 2, suggesting that these cells may be particularly vulnerable to SARS-CoV-2 infection (8).”
Vascular underpinning of COVID-19
Wazny, V. K., Siau, A., Wu, K. X., & Cheung, C. (2020) · Open Biology · doi:10.1098/rsob.200208 · Cited by 24
Lumpuy‐Castillo, J., Lorenzo-Almorós, A., Lázaro, A. M. P., Sánchez‐Ferrer, C. F., Egido, J., Tuñón, J., Peiró, C., & Lorenzo, Ó. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21186471 · Cited by 26
“dysfunction and acute myocardial injury are central events in the CV failure of COVID-19 patients [26].”
BackgroundBolay, H., Özge, A., Uludüz, D., & Baykan, B. B. (2020) · Headache The Journal of Head and Face Pain · doi:10.1111/head.13998 · Cited by 25
“Any injury to pericytes may lead to the endothelial and vascular dysfunction.(57) The dysfunctions of pericytes, expressing contractile properties, are linked to many microvascular diseases, including hypertension, diabetes, fibrosis, and inflammation.”
BackgroundInfluentialInflammation, immunity and potential target therapy of SARS-COV-2: A total scale analysis review
Smail, S. W., Saeed, M., Alkasalias, T., Khudhur, Z. O., Younus, D. A., Rajab, M. F., Abdulahad, W. H., Hussain, H. I., Niaz, K., & Safdar, M. (2021) · Food and Chemical Toxicology · doi:10.1016/j.fct.2021.112087 · Cited by 26
Verhoef, P. A., Kannan, S., Sturgill, J., Tucker, E. W., Morris, P. E., Miller, A. C., Sexton, T. R., Koyner, J. L., Hejal, R. B., Brakenridge, S. C., et al. (2021) · Critical Care Explorations · doi:10.1097/cce.0000000000000374 · Cited by 25
“ACE2 and TMPRSS2 are expressed in both tissues; although the myocardium could theoretically act as a host for SARSCoV-2, there are no documented reports myocardial infection (118, 119).”
BackgroundThe Mechanisms and Animal Models of SARS-CoV-2 Infection
Jia, W., Wang, J., Sun, B., Zhou, J., Shi, Y., & Zhou, Z. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.578825 · Cited by 27
“The SARS-CoV-2 variant containing the N501Y mutation could bind to mouse ACE2, causing wild-type mice to be infected with SARS-CoV-2 and develop interstitial pneumonia (Gu and Chen, 2020).”
BackgroundThe viral hypothesis in Alzheimer’s disease: SARS-CoV-2 on the cusp
Liu, N., Jiang, X., & Li, H. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1129640 · Cited by 27
“According to a meta-analysis of single single-cell sequencing data sets, ACE2 is expressed at low levels in the human posterior cingulate cortex and middle temporal gyrus (Chen et al., 2020).”
MethodCOVID-19 and Cardiovascular Diseases: From Cellular Mechanisms to Clinical Manifestations
Shu, H., Zheng, W., Li, N., Zhang, Z., Ceesay, B. M., Peng, Y., Zhou, N., & Wang, D. W. (2023) · Aging and Disease · doi:10.14336/ad.2023.0314 · Cited by 25
“In myocardial tissue, pericyte-specific and highly expressed ACE2 spreads outside endothelial cells of capillaries and venules, which may play an essential role in endothelial injury [123].”
BackgroundChen, Y., Ouyang, L., Bao, F. S., Li, Q., Han, L., Zhu, B., Ge, Y., Robinson, P. A., Xu, M. J., Liu, J., et al. (2020) · SSRN Electronic Journal · doi:10.2139/ssrn.3638427 · Cited by 27
Momtazi‐Borojeni, A. A., Banach, M., Reiner, Ž., Pirro, M., Bianconi, V., Al‐Rasadi, K., & Sahebkar, A. (2020) · Angiology · doi:10.1177/0003319720952284 · Cited by 24
“Patients with pre-existing CVD have increased ACE2 expression at both messenger RNA and protein levels.(26) On the other hand, CVD-associated ACE2 polymorphisms influence the affinity for the S-protein.”
BackgroundInfluentialPrognostic Value of Troponin Elevation in COVID-19 Hospitalized Patients
Cordeanu, E., Duthil, N., Séverac, F., Lambach, H., Tousch, J., Jambert, L., Mirea, C., Delatte, A., Younes, W., Frantz, A., et al. (2020) · Journal of Clinical Medicine · doi:10.3390/jcm9124078 · Cited by 24
“Endothelial and myocardial expression of ACE2 could account for myocardial injury, defined by a rise in troponin (Tn) associated with some severe forms of COVID-19 [5,6].”
BackgroundStroke in SARS-CoV-2 Infection: A Pictorial Overview of the Pathoetiology
Neshin, S. A. S., Shahjouei, S., Koza, E., Friedenberg, I., Khodadadi, F., Sabra, M., Kobeissy, F. H., Ansari, S., Tsivgoulis, G. K., Li, J., et al. (2021) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2021.649922 · Cited by 25
“However, ACE2 upregulation has been noted due to shear stress in the 3-dimensional model of the middle cerebral artery, particularly in stenotic portions.”
BackgroundInfluentialArévalos, V., Ortega‐Paz, L., Fernández-Rodríguez, D., Díaz, V. A. J., Bañeras, J., Campo, G. C., Rodríguez-Santamarta, M., de Prado, A. P., Gómez-Menchero, A. E., Fernández, J. F. D., et al. (2021) · PLoS ONE · doi:10.1371/journal.pone.0255263 · Cited by 24
“This may increase Ang II activity, which continues stimulating renin-angiotensin-aldosterone system (RAAS) with deleterious effects on heart and blood vessels [2–4].”
An Overview on the Epidemiology and Immunology of COVID-19
Meskini, M., Rami, M. R., Maroofi, P., Ghosh, S. B., Siadat, S. D., & Sheikhpour, M. (2021) · Journal of Infection and Public Health · doi:10.1016/j.jiph.2021.07.021 · Cited by 28
Pericytes: Intrinsic Transportation Engineers of the CNS Microcirculation
Eltanahy, A. M., Koluib, Y. A., & Gonzales, A. L. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.719701 · Cited by 27
Roles of inflammasomes in viral myocarditis
Xu, J., Zhou, Z., Zheng, Y., Yang, S., Huang, K., & Li, H. (2023) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2023.1149911 · Cited by 25
“Moreover, COVID-19-related myocarditis has aroused increasing attention (Siripanthong et al., 2020; Chen et al., 2020; Inciardi et al., 2020; Long et al., 2020).”
BackgroundThe roles of the kynurenine pathway in COVID-19 neuropathogenesis
Dehhaghi, M., Heydari, M., Panahi, H. K. S., Lewin, S. R., Heng, B., Brew, B. J., & Guillemin, G. J. (2024) · Infection · doi:10.1007/s15010-024-02293-y · Cited by 25
“For example, the proviral factor TiPARP, which modifies the gene expression of the cytokines IL-1β, IL-10 and TNF-α [80, 84] then induces IDO-1, resulting in further over-acti-vation of AhR and leads to an IDO1-AhR-IDO-1 positive feedback loop.”
BackgroundCrosstalk Between Coronavirus Disease 2019 and Cardiovascular Disease and Its Treatment
Ye, Q., Lu, D., Shang, S., Fu, J., Gong, F., Shu, Q., & Mao, J. (2020) · ESC Heart Failure · doi:10.1002/ehf2.12960 · Cited by 24
“Experimental research also found that patients with basic heart diseases exhibited increased expression of angiotensin-converting enzyme 2 (ACE2) and a high probability of heart attack and progression to severe disease after SARS-CoV-2 infection.(16) The assessment of ACE2 expres-”
BackgroundGamut of Cardiac Manifestations and Complications of COVID-19: A Contemporary Review
Rodriguez, J. B. C., Lange, R. A., & Mukherjee, D. (2020) · Journal of Investigative Medicine · doi:10.1136/jim-2020-001592 · Cited by 25
Szarpak, Ł., Filipiak, K. J., Skwarek, A., Pruc, M., Rahnama, M., Denegri, A., Jachowicz, M., Dawidowska, M., Gąsecka, A., Jaguszewski, M. J., et al. (2021) · Cardiology Journal · doi:10.5603/cj.a2021.0167 · Cited by 23
Zhang, G., Cui, X., Zhang, L., Liu, G., Zhu, X., Shangguan, J., Zhang, W., Zheng, Y., Zhang, H., Tang, J., et al. (2022) · ESC Heart Failure · doi:10.1002/ehf2.14003 · Cited by 24
“the pericytes-mediated microcirculation disorder, increasing the risk of heart attack and severe consequences.(5,6) Multiple studies have revealed that HF, as a common complication, is associated with poor prognosis of COVID-19 patients.”
BackgroundFabi, M., Petrović, B., Andreozzi, L., Corinaldesi, E., Filice, E., Biagi, C., Rizzello, A., Mattesini, B. E., Bugani, S., & Lanari, M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231710106 · Cited by 23
“Acute COVID-19 (AC19) in adults is known to be associated with endothelial injury in different organs, such as the lungs, kidneys and small bowel [17,18].”
BackgroundLong-Term effects of COVID-19: a review of current perspectives and mechanistic insights
Lenz, C., Slack, M., Shea, K. M., Reinert, R. R., Taysi, B. N., & Swerdlow, D. L. (2023) · Critical Reviews in Microbiology · doi:10.1080/1040841x.2023.2190405 · Cited by 28
“SARS-CoV-2 entry into cardiovascular cells is facilitated by ACE2 on surfaces of myocytes, coronary endothelial cells, pericytes, and arterial smooth muscle, increasing risk of organ damage and myocardial infarction (Chen et al. 2020; Cormican et al. 2021).”
BackgroundMicrofluidic Organ-Chips and Stem Cell Models in the Fight Against COVID-19
Satta, S., Rockwood, S. J., Wang, K., Wang, S., Mozneb, M., Arzt, M., Hsiai, T. K., & Sharma, A. (2023) · Circulation Research · doi:10.1161/circresaha.122.321877 · Cited by 23
Arginase inhibition by (−)-Epicatechin reverses endothelial cell aging
Garate‐Carrillo, A., Navarrete-Yañez, V., Ortiz-Vilchis, P., Guevara, G., Castillo, C., Mendoza‐Lorenzo, P., Ceballos, G. M., Ortíz-Flores, M., Nájera, N., Bustamante-Pozo, M. M., et al. (2020) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2020.173442 · Cited by 23
“EnD is also a hallmark of diseases such as atherosclerosis, hypertension and diabetes and may be an important pathophysiological element of COVID-19 disease (Chen and Li, 2020; Guzik et al., 2020; Whyte et al., 2020).”
Liu, J., Zhang, L., Chen, Y., Wu, Z., Dong, X., Teboul, J., Zhang, S., Ye, X., Liu, Y., Wang, T., et al. (2020) · Respiratory Medicine · doi:10.1016/j.rmed.2020.106159 · Cited by 22
Pathophysiologic mechanisms of cerebral endotheliopathy and stroke due to Sars-CoV-2
Kakarla, V., Kaneko, N., Nour, M., Khatibi, K., Elahi, F. M., Liebeskind, D. S., & Hinman, J. D. (2021) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x20985666 · Cited by 23
“They are also implicated in the pathogenesis of Sars-CoV-2-associated myocarditis.(59) Single-cell sequencing databases of the mouse brain vasculature suggest that ACE2 is a predominant marker gene for pericytes and vascular smooth muscle cells.”
BackgroundAngeli, F., Marazzato, J., Verdecchia, P., Balestrino, A., Bruschi, C., Ceriana, P., Chiovato, L., Vecchia, L. A. D., Ponti, R. D., Fanfulla, F., et al. (2021) · European Journal of Internal Medicine · doi:10.1016/j.ejim.2021.04.007 · Cited by 22
Sex-Related Factors in Cardiovascular Complications Associated to COVID-19
Megiorni, F., Pontecorvi, P., Gerini, G., Anastasiadou, E., Marchese, C., & Ceccarelli, S. (2021) · Biomolecules · doi:10.3390/biom12010021 · Cited by 22
“The central role of inflammation in virus-mediated myocardial injury is sustained by increased concentrations of plasmatic cytokines, such as interleukin-6 (IL-6), in COVID19 patients with cardiac injury [109] and by the clinical evidence of an association between the cardiac damage marker cTn and known inflammatory m…”
BackgroundCardiovascular Health and Disease in the Context of COVID-19
Umbrajkar, S., Stankowski, R. V., Rezkalla, S. H., & Kloner, R. A. (2021) · Cardiology Research · doi:10.14740/cr1199 · Cited by 23
“In a study delineating ACE2 expression among different cell types in the heart, Chen et al demonstrated particularly high levels of ACE2 expression on pericytes and close interaction of pericytes and endothelial cells, suggesting that SARSCoV-2 infection of pericytes in the heart may cause rapid dysfunction of nearby…”
BackgroundAnimal models for SARS-Cov2/Covid19 research-A commentary
Jarnagin, K., Alvarez, O., Shresta, S., & Webb, D. R. (2021) · Biochemical Pharmacology · doi:10.1016/j.bcp.2021.114543 · Cited by 22
Ocular transmissibility of COVID-19: possibilities and perspectives
Davis, G., Li, K., Thankam, F. G., Wilson, D. R., & Agrawal, D. K. (2022) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-021-04336-6 · Cited by 21
Sardu, C., Marfella, R., Prattichizzo, F., Grotta, R. L., Paolisso, G., & Ceriello, A. (2022) · Journal of Clinical Medicine · doi:10.3390/jcm11061564 · Cited by 21
“These processes induced by hyperglycemia might promote a higher susceptibility to SARS-CoV-2 infection since the oligomerization augments the binding affinity to spike [13,33,34].”
BackgroundLazebnik, Y. A. (2021) · Oncotarget · doi:10.18632/oncotarget.28088 · Cited by 22
“For example, the fusion of endothelial cells to each other or to other cells carrying a spike receptor, including platelets [112] and pericytes [113], could result in thrombosis, while the fusion of neurons may lead to neurological manifestations.”
BackgroundPelisek, J., Reutersberg, B., Greber, U. F., & Zimmermann, A. (2022) · Clinical Science · doi:10.1042/cs20220235 · Cited by 23
Pieri, M., Vayianos, P., Nicolaidou, V., Felekkis, K. N., & Papaneophytou, C. P. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24032380 · Cited by 22
“Furthermore, a recent single-cell RNA-seq analysis of the heart revealed low levels of ACE2 in cardiac myocytes and elevated levels in pericytes, while it has been demonstrated that ACE2 was upregulated in failing hearts [41,42].”
Background
Metadata
- Authors
- Chen, L., Li, X., Chen, M., Feng, Y., & Xiong, C.
- Affiliations
- Fudan University (CN)
- Renmin University of China (CN)
- Corresponding author
- Chen, Liang
- Xiong, Chenglong
- Venue
- Cardiovascular Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2020-03-30
- Volume
- 116
- Issue
- 6
- Pages
- 1097-1100
- ISSN
- 0008-6363 (ISSN-L)
- 1755-3245
- PMC
- PMC7184507
- OpenAlex
- W3014027512
- Cited by
- 1,163
- References
- 7
- Citations by year
- 2026: 19 · 2025: 32 · 2024: 64 · 2023: 148 · 2022: 210 · 2021: 332 · 2020: 355
- FWCI
- 34.28
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- Cardiovascular Research (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81872673)
- National Key Research and Development Program of China (2017YFC1200203)
- Fudan University
- Topics
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
- Keywords
- ACE2, SARS-CoV-2, COVID-19 pandemic, cardiac injury, pericytes, microvascular dysfunction, heart failure, viral receptor expression, myocardial injury
- MeSH terms
- Betacoronavirus, Receptors, Coronavirus, Angiotensin-Converting Enzyme 2, COVID-19, SARS-CoV-2, Heart, Heart Diseases, Humans, Peptidyl-Dipeptidase A, Myocardium, Pneumonia, Viral, Receptors, Virus, Gene Expression, Coronavirus Infections, Pericytes, Gene Expression Profiling, Pandemics, Spike Glycoprotein, Coronavirus
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