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.
Highlights
Angiotensin (Ang) converting enzyme 2 (ACE2) is a protein found as both a membrane-associated and secreted enzyme in cardiac, vascular, pulmonary, neuronal, and reproductive organs [1]
In the renin-angiotensin-aldosterone system (RAS or RAAS), ACE2 catalyzes the conversion of AngII to Ang1–7, which acts as a vasodilator [2] and plays a critical role in the control of cardiovascular and renal functions by maintaining the physiological homeostasis of blood pressure (BP) and electrolyte balance [3]
To define an association between Ace2 and cardiovascular traits in the BXD mice, we performed Pearson correlation analysis of Ace2 mRNA level against cardiovascular traits collected by BP measurements, ECG tracings, and transthoracic echocardiography
Summary
Angiotensin (Ang) converting enzyme 2 (ACE2) is a protein found as both a membrane-associated and secreted enzyme in cardiac, vascular, pulmonary, neuronal, and reproductive organs [1]. In the renin-angiotensin-aldosterone system (RAS or RAAS), ACE2 catalyzes the conversion of AngII to Ang, which acts as a vasodilator [2] and plays a critical role in the control of cardiovascular and renal functions by maintaining the physiological homeostasis of blood pressure (BP) and electrolyte balance [3]. ACE2 counterbalances with ACE and functions as a negative regulator of the RAS [7], playing a critical protective role against heart failure with reduced and preserved ejection fraction, myocardial infarction, and hypertension as well as against lung disease and diabetes [8]. This study investigates the regulation, gene network, and associated pathways of ACE2 that may be involved in inflammatory and cardiovascular complications of COVID-19
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
