AUTHOR=Xu Fuyi , Gao Jun , Munkhsaikhan Undral , Li Ning , Gu Qingqing , Pierre Joseph F. , Starlard-Davenport Athena , Towbin Jeffrey A. , Cui Yan , Purevjav Enkhsaikhan , Lu Lu 

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

JOURNAL=Frontiers in Cardiovascular Medicine

VOLUME=7

YEAR=2020

URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2020.582949

DOI=10.3389/fcvm.2020.582949

ISSN=2297-055X

ABSTRACT=<p><bold>Background:</bold> 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.</p><p><bold>Methods:</bold> 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 <italic>Ace2</italic> regulation, gene pathway, and co-expression networks.</p><p><bold>Results:</bold> A wide range of variation was found in expression of <italic>Ace2</italic> among the BXD strains. Levels of <italic>Ace2</italic> expression are negatively correlated with cardiovascular traits, including systolic and diastolic blood pressure and P wave duration and amplitude. <italic>Ace2</italic> co-expressed genes are significantly involved in cardiac- and inflammatory-related pathways. The eQTL mapping revealed that <italic>Cyld</italic> is a candidate upstream regulator for <italic>Ace2</italic>. Moreover, the protein–protein interaction (PPI) network analysis inferred several potential key regulators (<italic>Cul3, Atf2, Vcp, Jun, Ppp1cc, Npm1, Mapk8, Set, Dlg1, Mapk14</italic>, and <italic>Hspa1b</italic>) for <italic>Ace2</italic> co-expressed genes in the heart.</p><p><bold>Conclusions:</bold><italic>Ace2</italic> is associated with blood pressure, atrial morphology, and sinoatrial conduction in BXD mice. <italic>Ace2</italic> co-varies with <italic>Atf2, Cyld, Jun, Mapk8</italic>, and <italic>Mapk14</italic> 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.</p>