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Angiotensin-converting enzyme 2 (ACE2) was discovered in 2000 as a homologue enzyme to the better-known ACE, sharing many features of the enzymes belonging to the zinc metalloproteinase family. Similar to ACE, although soluble forms in plasma and urine are also found, ACE2 is a plasma membrane-bound ectoenzyme. Shedding of ACE2 has frequently been associated with the activity of tumor necrosis factor alpha-converting enzyme (TACE). In contrast to ACE, which has two active-site domains and functions as dicarboxipeptidase, ACE2 expresses only one catalytic site and acts as a monocarboxypeptidase, removing one amino acid from the C-terminus of its substrates. ACE2 metabolizes angiotensin I (Ang I) and angiotensin II (Ang II) into Ang-(1–9) and Ang-(1–7), separately, with higher preference for Ang II degradation. ACE2 has emerged as a potent negative regulator of the renin-angiotensin system (RAS), and the imbalanced activity of ACE/ACE2 systemically and/or locally has been proposed to be a significant contributor in many disease pathogeneses including inflammatory lung disease.
Figure 1. Pharmacological and genetic tools for the study of the ACE2/angiotensin-(1–7)/Mas axis.
ACE2 and heart and kidney diseases
In the heart, ACE2 takes part in structural and functional regulation, because mice with genetic deletion of ACE2 gene exhibited decreased cardiac contractility in line with high circulating and cardiac levels of Ang II. These mice also had increased expression of genes induced by hypoxia, a condition that causes vasoconstriction, endothelial dysfunction, and cardiac hypoperfusion. The lack of ACE2 also elicited inflammatory response in the infarct and peri-infarct regions, resulting in neutrophilic infiltration, upregulation of interferon-gamma and monocyte chemoattractant protein-1, and augmented phosphorylation of JNK1/2 and ERK1/2 signaling pathways. Treatment with ACE inhibitors prevented left ventricular hypertrophy and increased ACE2 expression in experimental myocardial infarction. Therefore, ACE2 overexpression prevented collagen accumulation, myocardial fibrosis, cardiomyocyte hypertrophy and improved left ventricular remodeling and function in diabetic cardiomyopathy.
Many studies have also showed a protective role for ACE2 in different models of renal diseases, including ischaemia and reperfusion kidney injury, subtotal nephrectomy, and unilateral ureteral obstruction. A possible explanation for renal lesion and proteinuria detected in animal models of acquired or genetic deficiency of ACE2 may be attributed to the abnormal predominance of deleterious actions of Ang II. Xanthenone (XNT) and diminazene (DIZE) are ACE2 inhibitors. Studies found that the acute in vivo administration of XNT to spontaneously hypertensive rats led to improvements in their cardiac function and reduced their blood pressure. Besides, recently researches confirmed a lack of enhancement of ACE2 enzymatic activity by XNT and DIZE in vitro and ex vivo experiments in both mice and rat kidney.
ACE2 and SARS coronavirus
Coronaviruses are a family of enveloped and positive-stranded RNA viruses that cause upper respiratory, gastrointestinal and central nervous system diseases in humans and other animals. The outbreak of SARS-CoV in 2002, MERS-CoV in 2012 and SARS-CoV-2 in 2019 suggested that coronaviruses can cross the species barrier and emerge as highly pathogenic viruses. The spike (S) protein of coronaviruses facilitates viral entry into target cells. Entry relies on binding of the surface unit, S1, of the S protein to a cellular receptor, which facilitates viral attachment to the surface of target cells. SARS-S engages ACE2 as entry receptor and employs the cellular serine protease TMPRSS2 for S protein priming. The SARS-S/ACE2 interface has been elucidated at the atomic level and the efficiency of ACE2 usage was found to be an important determinant of SARS-CoV transmissibility.
SARS-S und SARS-2-S share about 76% amino acid identity. The finding that SARS-2-S exploits ACE2 for entry, shows that the virus might target a similar spectrum of cells as SARS-CoV. In the lung, SARS-CoV infects mainly pneumocytes and macrophages. But ACE2 expression is not limited to the lung and extrapulmonary spread of SARS-CoV in ACE2+ tissues was observed. It has been suggested that the modest ACE2 expression in the upper respiratory tract could limit SARS-CoV transmissibility. Given the potentially increased transmissibility of SARS-CoV-2 relative to SARS-CoV, one may speculate that the new virus might exploit cellular attachment-promoting factors with higher efficiency as SARS-CoV to ensure robust infection of ACE2+ cells in the upper respiratory tract. It should be noted that ACE2 expression protects from lung injury and is downregulated by SARS-S, which might promote SARS. Thus, it will be interesting to determine whether SARS-CoV-2 also interferes with ACE2 expression.
ACE2 Gene Editing Service
CRISPR/Cas9 PlatformCB, a global leading biotechnological company specializing in gene editing, is dedicated to offering comprehensive CRISPR/Cas9 gene editing services and products for academic research, biotech research and pharmaceutical drug discovery. With deep gene editing knowledge and extensive experience in experimental operation and data processing, we help you effectively control ACE2 genes knockout/knockin/point mutation in cells or animals via CRISPR/Cas9 technology.
|Service||Details||Alternative cell lines or animal species|
|ACE2 Gene Editing Cell Line Generation||HEK239T, Hela, HepG2, U87, Ba/F3, CHO, MDA-MB-453, MDA-MB-231NIH3T3, T47D, Neuro2a, MCF7, RKO, K562, RAW264.7, etc.|
|ACE2 Gene Editing Animal Model Generation||Mouse, rat, rabbit, zebrafish, C. elegans, etc.|
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