The regulation of ACE-2 in the heart and lungs

The pathogenesis of SARS-CoV-2 infection or COVID-19 disease remains an active and rapidly evolving area of investigation. Currently, the angiotensin-converting enzyme 2 protein (ACE-2) is the primary receptor implicated in the pathogenesis of SARS-CoV-2. In normal physiological responses, the ACE-2 has important roles in regulating the renin-angiotensin systems (RAS) in several organs, including the heart, kidney, and lungs. Dysregulation of ACE-2 has been linked to heart failure, pulmonary hypertension, and diabetic cardiovascular complications. Two main risk factors for COVID-19 include hypertension and cardiovascular disease. However, the precise mechanism causing these risk factors for COVID-19 infectivity remains unknown. In this paper, we provide possible molecular mechanisms that underlie the cardiovascular risk factors for COVID-19.


IntroductIon
First reported in Wuhan, China, the SARS-CoV-2 (COVID- 19) virus has caused a worldwide pandemic leading to over one million deaths. The coronaviruses belong to a large family of single-stranded, positivesense RNA viruses that infect both humans and animals. COVID-19 is the seventh human corona virus to be identified. Patients infected with SARS-CoV-2 present with fever, cough, and difficulty breathing. Advanced stages of COVID-19 can lead to pneumonia, acute respiratory distress syndrome (ARDS), and congestive heart failure. 1 Although a novel virus, the SARS-CoV-2 virus shares a high level of genome sequence homology (70-80%) with SARS-CoV-1. 1 This similarity extends to the receptor essential for the SARS-CoV-1 and -2 pathogenesis, namely the angiotensin-converting enzyme 2 receptor (ACE-2). 1 The ACE-2 receptor is a type-1 transmembrane metallocarboxypeptidase that regulates blood pressure with ACE through the renin-angiotensin systems (RAS). 2 It is located in the vascular endothelial cells, the renal tubular epithelium, lung, kidney, gastrointestinal tract, and Leydig cells of the testes. [3][4][5] This receptor degrades angiotensin II to generate angiotensin 1-7 and angiotensin 1-9, thereby negatively regulating RAS ( Figure 1). 6,7 Specifically, angiotensin 1-7 and 1-9 are potent vasodilators in the heart, blood vessels, and kidneys. 8 Genetic mutations in the ACE-2 receptor have been linked to heart failure, systemic and pulmonary hypertension, myocardial infarction, and diabetic cardiovascular complications. 9 Clinical studies activating the ACE-2 receptor showed protective effects against hypertension and cardiovascular disease ( Figure 1). [9][10][11][12] In particular, two phase II clinical trials demonstrated that the administration of recombinant human ACE-2 reduced systemic inflammation and shifted RAS peptides away from angiotensin II to angiotensin 1-7. 13,14 In preclinical studies, activated ACE-2 decreased pulmonary injury and vascular damage and prevented pulmonary hypertension, decreased lung fibrosis and arterial remodeling, and improved right ventricular function ( Figure 1). [15][16][17] Given the COVID-19 pandemic, there is increased interest in understanding the ACE-2 receptor in the pathogenesis of SARS-CoV-2. In this paper, we summarize the normal physiological processes that regulate ACE-2 expression.

cArdIovAsculAr regulAtIon of Ace-2
Hypertension and cardiovascular disease are the major risk factors for COVID-19. [18][19][20][21] A study in Wuhan, China, showed that hypertension was associated with a hazard ratio of 1.70 and 1.82 for mortality and ARDS. 21 Subsequent studies found similar trends with increased hospital morbidity and mortality among COVID-19 patients with a history of hypertension. 18,20 It is hypothesized that older age and sex differences may account for increased mortality among COVID-19 patients with a history of hypertension. 18 Specifically, increases in ACE-2 expression may regulate the proliferation of smooth muscle cells and reduce the activity of angiotensin II with increased blood pressure. 22 In COVID-19 patients, the increase in ACE-2 expression may explain the increased susceptibility, morbidity, and mortality observed with hypertensive patients. However, this trend may exist in all organs. A murine study found that hypertension was caused by increased serum sodium levels and decreased ACE-2 expression in the kidneys. 23 Further study on hypertension and ACE-2 expression in different organs may provide more insight into the pathogenesis of SARS-CoV-2.
Several physiological processes regulate the expression on ACE-2 in the cardiovascular systems ( Figure 2A). A pre-clinical study using human aortic smooth muscle cells found that in comparison to the static conditions, the repeated physiological stretching (10% elongation at 1 Hz) increased ACE-2 expression and activity. 22 A similar study examining stretched cardiac smooth muscle cells also found that transcription factors such as activator protein 1 and nuclear factor-κB amplified the ACE-2 expression. 22 Additional studies showed that angiotensin II and endothelin-1 reduced ACE-2 levels via activation of extracellular signal-regulated kinase (ERK) 1/2 Figure 1. Role of ACE2 in the production of angiotensin 1-9 and 1-7 and their effect on the heart and lung health. and MAPK signaling pathways. 24,25 Therefore, it is believed that ACE-2 expression in the cardiovascular systems is regulated by several hypertrophic and anti-hypertrophic peptides. [24][25][26] A study examining the stress responsive protein deacetylase and mono-ADP ribosyltransferase enzyme, known as Sirtuin 6 (SIRT6), discovered that the enzyme reduced remodeling, fibrosis, and myocardial injury through activation of AMP-activated protein kinase (AMPK)-ACE2 signaling cascade. 27 Hypertensive mice treated with recombinant plasmids adeno-associated viral SIRT6vector had a decrease in ACE-2 expression. 27 Other studies found that inhibition of the Wnt signaling pathway reduced cardiac fibrosis and hypertrophy by regulating the ADAM17/ACE-2 pathway through ectodomain shedding. 28,29 Therefore, it is possible that other physiological mechanisms regulating ADAM17 expression may directly contribute to the susceptibility of patients to COVID-19, attributable to the modified ACE-2 expression. More research is needed to determine which regulatory mechanisms in the cardiovascular system increase the risk of COVID-19 morbidity and mortality.

Ace-2 regulAtIon In the lung
ACE-2 is highly expressed in the type I and type II alveolar epithelial cells of the lung. 30 The ACE-2 receptor protects the lung against injury through several mechanisms. The catalytic activity of ACE-2 degrades angiotensin II and prevents vasoconstriction, proapoptotic processes, and fibrotic processes in lung epithelial cells while simultaneously producing angiotensin 1-7. 31 Given the importance of ACE-2 in pulmonary physiology, the body actively regulates the expression of ACE-2 in alveolar cells (Figure 2). In particular, hypoxia stimulates the migration and proliferation of hematopoietic stem/progenitor cells through upregulation of the ACE-2 receptor. 32 It was later found that the hypoxia-inducible factor 1α (HIF-1α) was the key transcription factor that increased ACE-2 expression during hypoxia. 33 Therefore, it is possible that patients with chronic lung disease may have an increased expression of ACE-2 that increases their risk for infections from COVID-19.

future dIrectIons
Given the effects of SARS-CoV-2 on the heart and lungs, most studies have focused on the regulation of ACE-2 in these organ systems. However, there is an increasing evidence that metabolism may influence the expression of ACE-2 and the risk of infection. A recent meta-analysis of COVID-19 patients showed that obesity was a significant risk factor for mortality. 34 A similar finding of increased mortality among obese patients was observed in the H1N1 epidemic of 2009. 35 It is believed that obese individuals are at a higher risk for mortality from COVID-19 due to a combination of metabolic dysfunction, immune impairments, and adipose inflammation combined with physical and other medical comorbidities. 34 Several pre-clinical studies showed that other metabolic modulators, such as apelin, growth hormone, and SIRT1 (silent information regulator T1), increase ACE-2 expression. 36,37 It is possible that obesity may increase the risk of COVID-19 infection and mortality through an upregulation of ACE-2 receptors. For the foreseeable future, more investigation into the pathogenesis of COVID-19 will remain an integral component of identifying at risk patients and developing treatments.

conclusIon
The study of ACE-2 function in regular physiological responses provides possible mechanisms involved in SARS-CoV-2 infectivity and severity. In general, an increase in ACE-2 receptor would increase viral infection; specifically, a greater number of ACE-2 receptors increases the likelihood that SARS-CoV-2 will attach on epithelial surfaces and infect the host. In contrast, an increase in ACE-2 would reduce angiotensin II levels, which protects pulmonary epithelial cells. Given the importance of metabolic mediators in ACE-2 regulation, it is likely that multiple physiological functions influence the overall risk a given patient has for both contracting and developing severe COVID-19 disease. Furthermore, the time course of the SARS-CoV-2 virus may be another important factor for consideration. The COVID-19 disease occurs in two phases: the incubation and symptomatic phase. 38 The incubation phase lasts between 3-5 days during which the SARS-CoV-2 virus begins attaching to the pulmonary epithelial cells expressing ACE-2. A shorter or longer incubation period along with decreased or increased ACE-2 expression may both alter the overall risk of infectivity. During the symptomatic phase, it is unknown whether an increase in ACE-2 causes a corresponding increase in the infectivity of SARS-CoV-2. Further investigation on whether ACE-2 contributes to the pathogenesis after initial infection remains to be determined.