The Impact of Angiotensin-Converting Enzyme 2 (ACE2) Expression Levels in Patients with Comorbidities on COVID-19 Severity: A Comprehensive Review

Abstract

Angiotensin-Converting Enzyme 2 (ACE2) has been proved to be the main host cell receptor for the binding of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for the COVID-19 pandemic. The SARS-CoV-2 spike (S) protein binds to ACE2 to initiate the process of replication. This enzyme is widely present in human organ tissues, such as the heart and lung. The pathophysiology of ACE2 in SARS-CoV-2 infection is complex and may be associated with several factors and conditions that are more severe in COVID-19 patients, such as age, male gender, and comorbidities, namely, cardiovascular diseases, chronic respiratory diseases, obesity, and diabetes. Here we present a comprehensive review that aims to correlate the levels of expression of the ACE2 in patients with comorbidities and with a poor outcome in COVID-19 disease. Significantly higher levels of expression of ACE2 were observed in myocardial and lung tissues in heart failure and COPD patients, respectively. An age-dependent increase in SARS2-CoV-2 receptors in the respiratory epithelium may be also responsible for the increased severity of COVID-19 lung disease in elderly people. Although the role of ACE2 is highlighted regarding the damage that can arise upon the SARS-CoV-2 invasion, there was no association observed between renin-angiotensin-aldosterone system (RAAS) inhibitors and the severity of COVID-19.

The Drosophila melanogaster ACE2 ortholog genes are differently expressed in obesity/diabetes and aging models: Implications for COVID-19 pathology

“…5 D). Even though senescence is known to regulate the RAAS positively [4] , and there are some studies on the effect of sex on ACE2 levels [48] , [49] , the actual data on ACE2 mRNA expression across ages and sex are contradictory [50] , [51] , [52] .…”

Disrupting ACE2 Dimerization Mitigates the Infection by SARS-CoV-2 Pseudovirus

“…As a transmembrane zinc metallocarboxypeptidase, ACE2 is abundantly expressed in many organs/tissues and promotes cardioprotective actions of nitric oxide release, vasodilation, and the inhibition of inflammation by cleaving angiotensin II (Ang II) into Ang-(1-7) and Ang I into Ang-(1-9) (19,20). While the elevated level of ACE2 in patients with comorbidities is associated with an increased risk of SARS-CoV-2 infection and severity, the enzyme activity of ACE2 may be beneficial for patients suffering a dysfunctional renin-angiotensin-aldosterone system, which poses danger to infected patients with various comorbidities (21). Although evidence showing that ACE2 lacking Neck-domain maintains its peptidase activity (18), further investigation would be necessary to evaluate the potential impact of disturbing ACE2 dimerization to human health and to establish targeting the ACE2 dimerization as a potential therapeutic tool against SARS-CoV-2 infection.…”

COVID-19 disease and autoimmune disorders: A mutual pathway

“…The patients' differences in ACE2 receptor distribution and ACE2-SARS-CoV-2 mutual interactions could affect the disease pathophysiology, progression, and consequences. Many factors could affect ACE2 receptors distribution, including heritability, patient demographics, lifestyle, comorbidities, and drugs[ 13 ]. Meanwhile, soluble ACE-2 (sACE-2) is found in the serum or plasma due to shedding from the cell surface.…”