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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.

Background: Broad cellular functions and diseases including muscular dystrophy, arrhythmogenic right ventricular cardiomyopathy (ARVC5) and cancer are associated with transmembrane protein43 (TMEM43/LUMA). Objective: The study aimed to investigate biological roles of TMEM43 through genetic regulation, gene pathways and gene networks, candidate interacting genes and up- or down-stream regulators. Methods: Cardiac transcriptomes from 40 strains of recombinant inbred BXD mice and two parental strains representing murine genetic reference population (GRP) was applied for genetic correlation, functional enrichment and co-expression network analysis using systems genetics approach. The results were validated in a newly created knock-in Tmem43-S358L mutation mouse model (Tmem43S358L) that displayed signs of cardiac dysfunction, resembling ARVC5 phenotype seen in humans. Results: We found high Tmem43 levels among BXDs with broad variability in expression. Expression of Tmem43 highly negatively correlated with heart mass and heart rate among BXDs, while levels of Tmem43 highly positively correlated with plasma high density lipoproteins (HDL). Through finding differentially expressed genes (DEGs) between Tmem43S358L mutant and wild type (Tmem43WT) lines, 18 pathways (out of 42 found in BXDs GRP) that are involved in ARVC, Hypertrophic cardiomyopathy, Dilated cardiomyopathy, Non-alcoholic fatty liver disease, Alzheimer disease, Parkinson disease and Huntington disease were verified. We further constructed Tmem43-mediated gene network, in which Ctnna1, Adcy6, Gnas, Ndufs6 and Uqcrc2 were significantly altered in Tmem43S358L mice vs Tmem43WT controls. Conclusions: Our study defined the importance of Tmem43 for cardiac and metabolism related pathways, suggesting that cardiovascular disease-relevant risk factors may also increase risk of metabolic and neurodegenerative diseases via TMEM43-mediated pathways.