ACE2 interaction networks in COVID-19: a physiological framework for prediction of outcome in patients with cardiovascular risk factors

Abstract

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (coronavirus disease 2019; is associated with adverse outcome in patients with cardiovascular disease (CVD).Aim: To characterize the interaction between SARS-CoV-2 and Angiotensin Converting Enzyme 2 (ACE2) functional networks with focus on CVD.Methods: Using bioinformatic tools, network medicine approaches and publicly available datasets, we investigated ACE2 tissue expression and described ACE2 interaction network which could be affected by SARS-CoV-2 infection. We identified top ACE2 interactors, including miRNAs which are shared regulators between the ACE2, virus-infection related proteins and heart interaction networks, using lung and nervous system networks as a reference. We also identified main SARS-CoV-2 risk groups and performed drug predictions for them.Results: We found the same range of ACE2 expression confidence in respiratory and cardiovascular systems (averaging 4.48 and 4.64, respectively). Analysing the complete ACE2 interaction network, we identified 11 genes (ACE2, DPP4, ANPEP, CCL2, TFRC, MEP1A, ADAM17, FABP2, NPC1, CLEC4M, TMPRSS2) associated with virus-infection related processes. Previously described genes associated with cardiovascular risk factors DPP4, CCL2 and ANPEP were extensively connected with top regulators of ACE2 network, including ACE, INS and KNG1. Enrichment analysis revealed several disease phenotypes associated with interaction networks of ACE2, heart tissue, and virus-infection related protein, with the strongest associations with the following diseases (in decreasing rank order): obesity, hypertensive disease, noninsulin dependent diabetes mellitus, congestive heart failure, and coronary artery disease. We described for the first time microRNAs-miR (miR-302c-5p, miR-1305, miR-587, miR-26b-5p, and mir-27a-3p), which were common regulators of the three networks: ACE2, heart tissue and virus-infection related proteins.Conclusion: Our study provides novel information regarding the complexity of signaling pathways affected by SARS-CoV-2 and proposes predictive tools as miR towards personalized diagnosis and therapy in COVID-19. Additionally, our study provides a list of miRNAs with biomarker potential in prediction of adverse outcome in patients with COVID-19 and CVD.

Neurological manifestations of COVID-19: available evidences and a new paradigm

“…Simultaneously, any change in the expression of the genes directly interacting with COVID-19 receptors possibly might not allow the binding of virus to the receptors and can serves as a potential therapeutic target. We retrieved the list of genes interacting with ACE2 and TMPRSS2 receptors from multiple literatures, uniport database, and string database (Wicik et al 2020;Consortium 2019;Szklarczyk et al 2015). Out of 73 genes showing their expression in brain, we identified that a gene Integrin beta-1 (ITGB1) has a direct interaction with ACE2 receptor (Fig.…”

Potential role of ACE2-related microRNAs in COVID-19-associated nephropathy

“…As an impact of SARS-CoV-2 infection, ACE2 pathways downregulation lead to myocardial injury, fibrosis, and inflammation [ 1 , 4 , 19 ]. In line with these findings, several reports linked SARS-CoV-2 infection with myocardial damage and heart failure, accompanied by acute respiratory distress syndrome (ARDS), arrhythmias, coagulopathy, and acute kidney injury (AKI) [ 19 , 70 , 71 ]. Some previous studies have shown that SARS-CoV-2 directly or indirectly affect the kidneys and cause podocyte injury.…”

“…The ACE2 is widely expressed in lungs, heart tissue, intestine, kidneys, central nervous system, testis, and liver. During the 20 years from its discovery, the investigations targeting the enzyme's complex role established ACE2 as an important regulator in hypertension, heart failure (HF), myocardial infarction (MI), DM, and lung diseases [ 19 , 134 , 135 ]. Some evidences showed that ACE2 provides vascular protective effects by counteracting the essential effects of Ang II.…”

“…Using data mining and bioinformatic tools, Wicik et al described the ACE2 interaction network and evaluated its expression [ 19 ]. The study found 1954 miRNAs regulating components of the ACE2 interaction network [ 19 ].…”

“…Also, within the cell, the virus undergoes nuclear replication (by sending the genetic material to the nucleus) and released out of the cell after maturation [ 1 , 4 ]. Therefore, the link between cardiovascular complications and infection is related to ACE2, which is found to be a functional receptor for SARS-CoV-2 [ 18 , 19 ].…”