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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.

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