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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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InfluentialSex Differences in COVID-19 Hospitalization and Mortality
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Alternative Renin-Angiotensin System
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“108,109 Size-exclusion chromatography and cryoelectron microscopy showed that ACE2 forms a dimer, 110,111 but there are also reports of it being a monomer in the plasma membrane.”
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“30 More research is needed to assess to what extent ACE2 surface expression or polymorphisms, or other coreceptors and proteoglycan moieties, are markers of tissue susceptibility.”
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“In human heart, vascular pericytes demonstrate abundant ACE2 expression (Chen et al. 2020).”
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“1), which is consistent with the role for AhR activation in the host response to CoV infection (Chen et al., 2020; Grunewald, Shaban, Mackin, Fehr, & Perlman, 2020; Neavin, Liu, Ray, & Weinshilboum, 2018).”
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“Research has also shown that SARS-CoV-2 can infect many organs other than the lungs, including the heart, and induce dysfunction of these organs [38,39].”
Cerebral Venous Thrombosis in COVID-19: A New York Metropolitan Cohort Study
Al‐Mufti, F., Amuluru, K., Sahni, R., Bekelis, K., Karimi, R., Ogulnick, J. V., Cooper, J., Overby, P. J., Nuoman, R., Tiwari, A., et al. (2021) · American Journal of Neuroradiology · doi:10.3174/ajnr.a7134 · Cited by 69
“The virus may initially invade endothelial cells through angiotensinconverting enzyme receptors.(45) The presence of viral elements within endothelial cells and an accumulation of inflammatory cells, with evidence of inflammatory cell death, have been demonstrated in patients with COVID-19.”
BackgroundCovid-19 and development of heart failure: mystery and truth
Onohuean, H., Al-Kuraishy, H. M., Al-Gareeb, A. I., Qusti, S. Y., Alshammari, E. M., & Batiha, G. E. (2021) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-021-02147-6 · Cited by 69
COVID-19: Are we dealing with a multisystem vasculopathy in disguise of a viral infection?
Mondal, R., Lahiri, D., Deb, S., Bandyopadhyay, D., Shome, G., Sarkar, S., Paria, S. R., Thakurta, T. G., Singla, P., & Biswas, S. C. (2020) · Journal of Thrombosis and Thrombolysis · doi:10.1007/s11239-020-02210-8 · Cited by 69
Elucidating the Neuropathologic Mechanisms of SARS-CoV-2 Infection
Pacheco‐Herrero, M., Soto-Rojas, L. O., Harrington, C. R., Flores-Martinez, Y. M., Villegas-Rojas, M. M., León-Aguilar, A. M., Martínez-Gómez, P. A., Campa-Córdoba, B. B., Apátiga-Pérez, R., Corniel-Taveras, C. N., et al. (2021) · Frontiers in Neurology · doi:10.3389/fneur.2021.660087 · Cited by 71
“These areas include the olfactory bulb, choroid plexus, cerebral cortex, caudate/putamen, ventral striatum, thalamus, hypothalamus (paraventricular nuclei), spinal cord, hippocampus, frontal cortex (52, 95, 100), substantia nigra, middle temporal gyrus (64, 101), and other brain areas (Table 1).”
BackgroundSharafati, A., Asadollah, S. B. H. S., & Al-Ansari, N. A. (2021) · Ain Shams Engineering Journal · doi:10.1016/j.asej.2021.03.028 · Cited by 68
Is Ferroptosis a Key Component of the Process Leading to Multiorgan Damage in COVID-19?
Pasini, A. M. F., Stranieri, C., Girelli, D., Busti, F., & Cominacini, L. (2021) · Antioxidants · doi:10.3390/antiox10111677 · Cited by 72
Oussalah, A., Gleye, S., Clerc‐Urmès, I., Laugel, E., Callet, J., Barbé, F., Orlowski, S., Malaplate, C., Aimone‐Gastin, I., Fofou‐Caillierez, M. B., et al. (2020) · Clinical Infectious Diseases · doi:10.1093/cid/ciaa677 · Cited by 68
Torices, S., Cabrera, R., Stangis, M., Naranjo, O., Fattakhov, N. S., Téglás, T., Adesse, D., & Toborek, M. J. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02210-2 · Cited by 65
Fu, Y., & Xiong, S. (2021) · Journal of Controlled Release · doi:10.1016/j.jconrel.2021.05.049 · Cited by 67
“cardiac injury in patients with SARS-CoV-2 infection were common for observation [2,49].”
Cooper, S. L., Boyle, E., Jefferson, S. R., Heslop, C., Mohan, P., Mohanraj, G. G. J., Sidow, H. A., Tan, R. C. P., Hill, S. J., & Woolard, J. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22158255 · Cited by 70
“Sequentially, this increases the level of viral replication and subsequently, viral load, which has been implicated in COVID-19 severity [143,149].”
BackgroundCardiac Troponin-I and COVID-19: A Prognostic Tool for In-Hospital Mortality
Abbasi, B. A., Torres, P., Tuarez, F. J. R., Dewaswala, N., Abdallah, A., Chen, K., Qader, M. A., Job, R., Aboulenain, S., Dziadkowiec, K. N., et al. (2020) · Cardiology Research · doi:10.14740/cr1159 · Cited by 66
Prevalence and outcome of dysnatremia in patients with COVID-19 compared to controls
Atila, C., Sailer, C. O., Bassetti, S., Tschudin‐Sutter, S., Bingisser, R. M., Siegemund, M., Osswald, S., Rentsch, K., Rueegg, M., Schaerli, S., et al. (2021) · European Journal of Endocrinology · doi:10.1530/eje-20-1374 · Cited by 64
Epithelial and Endothelial Expressions of ACE2: SARS-CoV-2 Entry Routes
Güney, C., & Akar, F. (2021) · Journal of Pharmacy & Pharmaceutical Sciences · doi:10.18433/jpps31455 · Cited by 66
“On the contrary, high expression of ACE2 in the heart and lung tissues of patients with comorbidities associated with severe COVID-19 was proposed to increase deleterious effect of virus infection by facilitating the SARSCoV-2 entry into cells (63, 64).”
BackgroundLassen, M. C. H., Skaarup, K. G., Lind, J. N., Alhakak, A. S., Sengeløv, M., Nielsen, A. B., Simonsen, J. Ø., Johansen, N. D., Davidovski, F. S., Christensen, J., et al. (2021) · European Journal of Heart Failure · doi:10.1002/ejhf.2347 · Cited by 66
Role of microRNAs in COVID-19 with implications for therapeutics
Arghiani, N., Nissan, T. A., & Matin, M. M. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.112247 · Cited by 65
“ACE2 receptors are widely expressed in the vascular endothelium and cardiomyocytes that are involved in heart function and diabetes mellitus [2,31,105,106].”
Extracellular vesicles mediate antibody-resistant transmission of SARS-CoV-2
Xia, B., Pan, X., Luo, R., Shen, X., Li, S., Wang, Y., Zuo, X., Wu, Y. L., Guo, Y., Xiao, G., et al. (2023) · Cell Discovery · doi:10.1038/s41421-022-00510-2 · Cited by 67
SARS-CoV-2 spike protein induces IL-18-mediated cardiopulmonary inflammation via reduced mitophagy
Liang, S., Bao, C., Yang, Z. F., Liu, S., Sun, Y., Cao, W., Wang, T., Schwantes-An, T.-H. L., Choy, J. S., Naidu, S. R., et al. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01368-w · Cited by 73
Endothelial dysfunction in Coronavirus disease 2019 (COVID-19): Gender and age influences
Froldi, G., & Dorigo, P. (2020) · Medical Hypotheses · doi:10.1016/j.mehy.2020.110015 · Cited by 68
Chen, J., Bai, H., Liu, J., Chen, G., Liao, Q., Yang, J., Wu, P., Wei, J., Ma, D., Chen, G., et al. (2020) · Clinical Infectious Diseases · doi:10.1093/cid/ciaa920 · Cited by 65
“Additionally, angiote sin-converting enzyme 2 (ACE2) is the receptor-binding domain for SARS-CoV-2 [23], thus, the expression pattern of ACE2 in difference organs and individuals might account for the susceptibility, severity and outcome of SARS-CoV-2 infectious pneumonia [24,25].”
BackgroundHyperoxia and modulation of pulmonary vascular and immune responses in COVID-19
Hanidziar, D., & Robson, S. C. (2020) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00304.2020 · Cited by 69
Expression Analyses of MicroRNAs in Hamster Lung Tissues Infected by SARS-CoV-2
Kim, W. R., Park, E. G., Kang, K.-W., Lee, S., Kim, B., & Kim, H. (2020) · Molecules and Cells · doi:10.14348/molcells.2020.0177 · Cited by 65
“Genome sequence analysis demonstrated that SARS-CoV, MERS-CoV, and SARSCoV-2 belong to the beta-coronavirus genus (Chen et al., 2020c; Munster et al., 2020).”
BackgroundInfluentialNicotine and the nicotinic cholinergic system in COVID‐19
Tizabi, Y., Getachew, B., Copeland, R., & Aschner, M. (2020) · FEBS Journal · doi:10.1111/febs.15521 · Cited by 66
Darwesh, A. M., Bassiouni, W., Sosnowski, D. K., & Seubert, J. M. (2020) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2020.107703 · Cited by 66
“Patients with comorbidities such as diabetes, dyslipidemia, aberrations in plasma cholesterol and triglycerides and coronary heart disease aremore susceptible to severe COVID-19 outcomes such as cardiac complications, sepsis, ARDS and death (Chen et al., 2020; Petersen et al., 2020; Shi et al., 2020; Wang, Hu, et al.,…”
Immunosenescence in atherosclerosis: A role for chronic viral infections
Talepoor, A. G., & Doroudchi, M. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.945016 · Cited by 65
Immunoinflammatory, Thrombohaemostatic, and Cardiovascular Mechanisms in COVID-19
Gencer, S., Lacy, M., Atzler, D., van der Vorst, E. P. C., Döring, Y., & Weber, C. (2020) · Thrombosis and Haemostasis · doi:10.1055/s-0040-1718735 · Cited by 66
The cardiovascular aspect of COVID-19
Adu‐Amankwaah, J., Mprah, R., Adekunle, A. O., Noah, M. L. N., Adzika, G. K., Machuki, J. O., & Sun, H. (2020) · Annals of Medicine · doi:10.1080/07853890.2020.1861644 · Cited by 62
“This may be similar to what is seen in many patients with acute respiratory illnesses, or it may show myocardial injury since the virus binds to ACE2 receptors, which are widely expressed in the pericytes of the heart [29,46,58].”
Atrial fibrillation in COVID‐19: A review of possible mechanisms
Stone, E., Kiat, H., & McLachlan, C. S. (2020) · The FASEB Journal · doi:10.1096/fj.202001613 · Cited by 61
Coronary heart disease and COVID-19: A meta-analysis
Liang, C., Zhang, W., Li, S., & Qin, G. (2021) · Medicina Clínica · doi:10.1016/j.medcli.2020.12.017 · Cited by 61
Bos, J. M., Hebl, V. B., Oberg, A. L., Sun, Z., Herman, D. S., Teekakirikul, P., Seidman, J. G., Seidman, C. E., dos Remedios, C. G., Maleszewski, J. J., et al. (2020) · Mayo Clinic Proceedings · doi:10.1016/j.mayocp.2020.04.028 · Cited by 64
Gaussen, A., Hornby, L., Rockl, G., O’Brien, S. F., Delage, G., Sapir‐Pichhadze, R., Drews, S. J., Weiss, M. J., & Lewin, A. (2021) · Transplantation · doi:10.1097/tp.0000000000003744 · Cited by 62
“61,62 Immunostaining has detected ACE2 protein expression in small capillaries and cardiomyocytes.”
COVID-19 and myocarditis: a review of literature
Ali, M., Shiwani, H. A., Elfaki, M. Y., Hamid, M., Pharithi, R. B., Kamgang, R., Egom, C. B.-A., Oyono, J. L. E., & Egom, E. E. A. (2022) · The Egyptian Heart Journal · doi:10.1186/s43044-022-00260-2 · Cited by 62
Cardiac Arrhythmias in Post-COVID Syndrome: Prevalence, Pathology, Diagnosis, and Treatment
Huseynov, A., Akın, İ., Duerschmied, D., & Scharf, R. E. (2023) · Viruses · doi:10.3390/v15020389 · Cited by 68
“Based on gene expression studies, the human ventricular myocardium also contains the requisite mediators of SARS-CoV-2 binding and entry [26].”
BackgroundModeling Heart Diseases on a Chip: Advantages and Future Opportunities
Mourad, O., Yee, R., Li, M., & Nunes, S. S. (2023) · Circulation Research · doi:10.1161/circresaha.122.321670 · Cited by 62
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Lu, R. X. Z., Lai, B. F. L., Rafatian, N., Gustafson, D., Campbell, S. B., Banerjee, A., Kozak, R., Mossman, K., Mubareka, S., Howe, K. L., et al. (2022) · Lab on a Chip · doi:10.1039/d1lc00817j · Cited by 58
The Rationale for Potential Pharmacotherapy of COVID-19
Saber-Ayad, M. M., Saleh, M. A., & Abu‐Gharbieh, E. (2020) · Pharmaceuticals · doi:10.3390/ph13050096 · Cited by 59
“Similar to SARS-CoV, SARS-CoV-2 binds first with its S (Spike) glycoprotein to Angiotensin- Converting Enzyme 2 (ACE-2), a homologs enzyme to ACE expresses on the membrane of lung epithelial cells which is followed by virus-cell fusion and viral entry, Figure-1, (125-128).”
BackgroundLazaridis, C., Vlachogiannis, N. I., Bakogiannis, C., Spyridopoulos, I., Stamatelopoulos, K. S., Kanakakis, I., Vassilikos, V. P., & Stellos, K. (2020) · Hellenic Journal of Cardiology · doi:10.1016/j.hjc.2020.05.004 · Cited by 60
Tackling COVID‐19 infection through complement‐targeted immunotherapy
Jodele, S., & Köhl, J. (2020) · British Journal of Pharmacology · doi:10.1111/bph.15187 · Cited by 58
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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