The Genetic Dissection of Ace2 Expression Variation in the Heart of Murine Genetic Reference Population

Abstract

Background: A high inflammatory and cytokine burden that induces vascular inflammation, myocarditis, cardiac arrhythmias, and myocardial injury is associated with a lethal outcome in COVID-19. The SARS-CoV-2 virus utilizes the ACE2 receptor for cell entry in a similar way to SARS-CoV. This study investigates the regulation, gene network, and associated pathways of ACE2 that may be involved in inflammatory and cardiovascular complications of COVID-19.Methods: Cardiovascular traits were determined in the one of the largest mouse genetic reference populations: BXD recombinant inbred strains using blood pressure, electrocardiography, and echocardiography measurements. Expression quantitative trait locus (eQTL) mapping, genetic correlation, and functional enrichment analysis were used to identify Ace2 regulation, gene pathway, and co-expression networks.Results: A wide range of variation was found in expression of Ace2 among the BXD strains. Levels of Ace2 expression are negatively correlated with cardiovascular traits, including systolic and diastolic blood pressure and P wave duration and amplitude. Ace2 co-expressed genes are significantly involved in cardiac- and inflammatory-related pathways. The eQTL mapping revealed that Cyld is a candidate upstream regulator for Ace2. Moreover, the protein–protein interaction (PPI) network analysis inferred several potential key regulators (Cul3, Atf2, Vcp, Jun, Ppp1cc, Npm1, Mapk8, Set, Dlg1, Mapk14, and Hspa1b) for Ace2 co-expressed genes in the heart.Conclusions:Ace2 is associated with blood pressure, atrial morphology, and sinoatrial conduction in BXD mice. Ace2 co-varies with Atf2, Cyld, Jun, Mapk8, and Mapk14 and is enriched in the RAS, TGFβ, TNFα, and p38α signaling pathways, involved in inflammation and cardiac damage. We suggest that all these novel Ace2-associated genes and pathways may be targeted for preventive, diagnostic, and therapeutic purposes in cardiovascular damage in patients with systemic inflammation, including COVID-19 patients.

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“…The top related pathways included Staphylococcus aureus infection, the Hippo signaling pathway, the complement and coagulation cascades, ECM–receptor interaction, protein digestion, and protein absorption. Next, the top 192 genes were also submitted to NetworkAnalyst software (http://www.networkanalyst.ca) so that we could analyze the PPI network with regards to curated and nonredundant sets of protein interactions in the IMEx consortium database [19]. As shown in Figure 5C, there were 10 proteins at the central node of the network which exhibited the highest degree of connections to other genes: FN1 , FBLN1 , APP , CLU , DBN1 , LMO2 , GRB2 , TFAP2C , PDGFRB , and COL1A1 .…”

Ace2 and Tmprss2 Expressions Are Regulated by Dhx32 and Influence the Gastrointestinal Symptoms Caused by SARS-CoV-2

“…The eQTL mapping of the transcripts was performed in the GN, as described in our previous work [23,31,32]. Two methods were used for the eQTL mapping.…”

“…Each BXD strain is represented by a stable inbred strain (males and females are isogenic with the sole exception of the Y chromosome) that can be replicated in large numbers to reduce technical and environmental sources of variance. We successfully used the BXD family to perform the genetic dissection of Ace2 expression variation in the heart and lung [23] and to expand our understanding on causal models of viral infection and signaling that is relevant to cardiovascular and respiratory diseases.…”

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“…The potential targets of volatile oil active ingredients, insomnia targets, and the differential genes sequenced by the transcriptome were integrated, duplicate values were deleted, and their intersection was taken and imported into the String ( https://string-db.org/ ) database ( 19 , 20 ). Next, the minimum interaction threshold was set as “highest confidence” (>0.9), the free protein was hidden, the protein interaction map was obtained, and finally, the results were imported into Cytoscape 3.7.1 software to map their interaction network, the result shown in Figure 3C .…”