ACE2 Interaction Networks in COVID-19: A Physiological Framework for Prediction of Outcome in Patients with Cardiovascular Risk Factors

被引:81
作者
Wicik, Zofia [1 ,2 ]
Eyileten, Ceren [2 ]
Jakubik, Daniel [2 ]
Simoes, Sergio N. [3 ]
Martins, David C., Jr. [1 ]
Pavao, Rodrigo [1 ]
Siller-Matula, Jolanta M. [2 ,4 ]
Postula, Marek [2 ]
机构
[1] Fed Univ ABC, Ctr Matemat Computacao & Cognicao, BR-09606045 Santo Andre, SP, Brazil
[2] Med Univ Warsaw, Ctr Preclin Res & Technol CEPT, Dept Expt & Clin Pharmacol, PL-02091 Warsaw, Poland
[3] Fed Inst Educ Sci & Technol Espirito Santo, BR-29056264 Serra, ES, Brazil
[4] Med Univ Vienna, Dept Internal Med 2, Div Cardiol, A-1090 Vienna, Austria
关键词
ACE2; COVID-19; SARS-CoV-2; cardiovascular; gene expression; miRNA; therapeutic target; microRNA; miR; ACUTE RESPIRATORY SYNDROME; ANGIOTENSIN-CONVERTING ENZYME-2; ACUTE LUNG INJURY; SARS-COV; EXPRESSION; DISEASE; CELLS; ENTRY; RECEPTOR; PATHOGENESIS;
D O I
10.3390/jcm9113743
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (coronavirus disease 2019; COVID-19) is associated with adverse outcomes in patients with cardiovascular disease (CVD). The aim of the study was to characterize the interaction between SARS-CoV-2 and Angiotensin-Converting Enzyme 2 (ACE2) functional networks with a focus on CVD. Methods: Using the network medicine approach and publicly available datasets, we investigated ACE2 tissue expression and described ACE2 interaction networks that could be affected by SARS-CoV-2 infection in the heart, lungs and nervous system. We compared them with changes in ACE-2 networks following SARS-CoV-2 infection by analyzing public data of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). This analysis was performed using the Network by Relative Importance (NERI) algorithm, which integrates protein-protein interaction with co-expression networks. We also performed miRNA-target predictions to identify which miRNAs regulate ACE2-related networks and could play a role in the COVID19 outcome. Finally, we performed enrichment analysis for identifying the main COVID-19 risk groups. Results: We found similar ACE2 expression confidence levels in respiratory and cardiovascular systems, supporting that heart tissue is a potential target of SARS-CoV-2. Analysis of ACE2 interaction networks in infected hiPSC-CMs identified multiple hub genes with corrupted signaling which can be responsible for cardiovascular symptoms. The most affected genes were EGFR (Epidermal Growth Factor Receptor), FN1 (Fibronectin 1), TP53, HSP90AA1, and APP (Amyloid Beta Precursor Protein), while the most affected interactions were associated with MAST2 and CALM1 (Calmodulin 1). Enrichment analysis revealed multiple diseases associated with the interaction networks of ACE2, especially cancerous diseases, obesity, hypertensive disease, Alzheimer's disease, non-insulin-dependent diabetes mellitus, and congestive heart failure. Among affected ACE2-network components connected with the SARS-Cov-2 interactome, we identified AGT (Angiotensinogen), CAT (Catalase), DPP4 (Dipeptidyl Peptidase 4), CCL2 (C-C Motif Chemokine Ligand 2), TFRC (Transferrin Receptor) and CAV1 (Caveolin-1), associated with cardiovascular risk factors. We described for the first time miRNAs which were common regulators of ACE2 networks and virus-related proteins in all analyzed datasets. The top miRNAs regulating ACE2 networks were miR-27a-3p, miR-26b-5p, miR-10b-5p, miR-302c-5p, hsa-miR-587, hsa-miR-1305, hsa-miR-200b-3p, hsa-miR-124-3p, and hsa-miR-16-5p. Conclusion: Our study provides a complete mechanistic framework for investigating the ACE2 network which was validated by expression data. This framework predicted risk groups, including the established ones, thus providing reliable novel information regarding the complexity of signaling pathways affected by SARS-CoV-2. It also identified miRNAs that could be used in personalized diagnosis in COVID-19.
引用
收藏
页数:29
相关论文
共 110 条
[1]   COVID-19, Renin-Angiotensin System and Endothelial Dysfunction [J].
Amraei, Razie ;
Rahimi, Nader .
CELLS, 2020, 9 (07)
[2]  
[Anonymous], 2020, LANCET PSYCHIAT, DOI DOI 10.1016/S2215-0366(20)30287-X
[3]   Epidemiological, demographic, and clinical characteristics of 47 cases of Middle East respiratory syndrome coronavirus disease from Saudi Arabia: a descriptive study [J].
Assiri, Abdullah ;
Al-Tawfiq, Jaffar A. ;
Al-Rabeeah, Abdullah A. ;
Al-Rabiah, Fahad A. ;
Al-Hajjar, Sami ;
Al-Barrak, Ali ;
Flemban, Hesham ;
Al-Nassir, Wafa N. ;
Balkhy, Hanan H. ;
Al-Hakeem, Rafat F. ;
Makhdoom, Hatem Q. ;
Zumla, Alimuddin I. ;
Memish, Ziad A. .
LANCET INFECTIOUS DISEASES, 2013, 13 (09) :752-761
[4]   Network medicine: a network-based approach to human disease [J].
Barabasi, Albert-Laszlo ;
Gulbahce, Natali ;
Loscalzo, Joseph .
NATURE REVIEWS GENETICS, 2011, 12 (01) :56-68
[5]   COVID-19 and diabetes: Is this association driven by the DPP4 receptor? Potential clinical and therapeutic implications [J].
Barchetta, Ilaria ;
Cavallo, Maria Gisella ;
Baroni, Marco Giorgio .
DIABETES RESEARCH AND CLINICAL PRACTICE, 2020, 163
[6]   Mechanisms of Coronavirus Cell Entry Mediated by the Viral Spike Protein [J].
Belouzard, Sandrine ;
Millet, Jean K. ;
Licitra, Beth N. ;
Whittaker, Gary R. .
VIRUSES-BASEL, 2012, 4 (06) :1011-1033
[7]   Development and validation of plasma miRNA biomarker signature panel for the detection of early HIV-1 infection [J].
Biswas, Santanu ;
Haleyurgirisetty, Mohan ;
Lee, Sherwin ;
Hewlett, Indira ;
Devadas, Krishnakumar .
EBIOMEDICINE, 2019, 43 :307-316
[8]   SARS-CoV-2 infects and induces cytotoxic effacts in human cardiomyocytes [J].
Bojkova, Denisa ;
Wagner, Julian U. G. ;
Shumliakivska, Mariana ;
Aslan, Galip S. ;
Saleem, Umber ;
Hansen, Arne ;
Luxan, Guillermo ;
Gunther, Stefan ;
Pham, Minh Duc ;
Krishnan, Jaya ;
Harter, Patrick N. ;
Ermel, Utz H. ;
Frangakis, Achilleas S. ;
Milting, Hendrik ;
Zeiher, Andreas M. ;
Klingel, Karin ;
Cinatl, Jindrich ;
Dendorfer, Andreas ;
Eschenhagen, Thomas ;
Tschoepe, Carsten ;
Ciesek, Sandra ;
Dimmeler, Stefanie .
CARDIOVASCULAR RESEARCH, 2020, 116 (14) :2207-2215
[9]   Non-coding RNA therapeutics for cardiac regeneration [J].
Braga, Luca ;
Ali, Hashim ;
Secco, Ilaria ;
Giacca, Mauro .
CARDIOVASCULAR RESEARCH, 2021, 117 (03) :674-693
[10]   Evidence of SARS-CoV-2 Transcriptional Activity in Cardiomyocytes of COVID-19 Patients without Clinical Signs of Cardiac Involvement [J].
Bulfamante, Gaetano Pietro ;
Perrucci, Gianluca Lorenzo ;
Falleni, Monica ;
Sommariva, Elena ;
Tosi, Delfina ;
Martinelli, Carla ;
Songia, Paola ;
Poggio, Paolo ;
Carugo, Stefano ;
Pompilio, Giulio .
BIOMEDICINES, 2020, 8 (12) :1-13