ACE2 as therapeutic agent

Qiuhong Li; Maria B. Grant; Elaine M. Richards; Mohan K. Raizada

doi:10.1042/cs20200570

journal article Oct 01, 2020

ACE2 as therapeutic agent

Qiuhong Li

Maria B. Grant

Elaine M. Richards Mohan K. Raizada

Clinical Science Vol. 134 No. 19 pp. 2581-2595 · Portland Press Ltd.

View at Publisher Save 10.1042/cs20200570

Abstract

Abstract
The angiotensin-converting enzyme 2 (ACE2) has emerged as a critical regulator of the renin–angiotensin system (RAS), which plays important roles in cardiovascular homeostasis by regulating vascular tone, fluid and electrolyte balance. ACE2 functions as a carboxymonopeptidase hydrolyzing the cleavage of a single C-terminal residue from Angiotensin-II (Ang-II), the key peptide hormone of RAS, to form Angiotensin-(1-7) (Ang-(1-7)), which binds to the G-protein–coupled Mas receptor and activates signaling pathways that counteract the pathways activated by Ang-II. ACE2 is expressed in a variety of tissues and overwhelming evidence substantiates the beneficial effects of enhancing ACE2/Ang-(1-7)/Mas axis under many pathological conditions in these tissues in experimental models. This review will provide a succinct overview on current strategies to enhance ACE2 as therapeutic agent, and discuss limitations and future challenges. ACE2 also has other functions, such as acting as a co-factor for amino acid transport and being exploited by the severe acute respiratory syndrome coronaviruses (SARS-CoVs) as cellular entry receptor, the implications of these functions in development of ACE2-based therapeutics will also be discussed.

Topics

No keywords indexed for this article. Browse by subject →

References

176

[1]

Mehta "Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system" Am. J. Physiol. Cell Physiol. (2007) 10.1152/ajpcell.00287.2006

[2]

Forrester "Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology" Physiol. Rev. (2018) 10.1152/physrev.00038.2017

[3]

Paul "Physiology of local renin-angiotensin systems" Physiol. Rev. (2006) 10.1152/physrev.00036.2005

[4]

Bader "Tissue renin-angiotensin-aldosterone systems: Targets for pharmacological therapy" Annu. Rev. Pharmacol. Toxicol. (2010) 10.1146/annurev.pharmtox.010909.105610

[5]

Nehme "An Update on the Tissue Renin Angiotensin System and Its Role in Physiology and Pathology" J Cardiovasc Dev Dis (2019)

[6]

Donoghue "A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9" Circ. Res. (2000) 10.1161/01.res.87.5.e1

[7]

A Human Homolog of Angiotensin-converting Enzyme

Sarah R. Tipnis, Nigel M. Hooper, Ralph Hyde et al.

Journal of Biological Chemistry 2000 10.1074/jbc.m002615200

[8]

Vickers "Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase" J. Biol. Chem. (2002) 10.1074/jbc.m200581200

[9]

Angiotensin-(1–7) is an endogenous ligand for the G protein-coupled receptor Mas

Robson A. S. Santos, Ana C. Simoes e Silva, Christine Maric et al.

Proceedings of the National Academy of Sciences 2003 10.1073/pnas.1432869100

[10]

The ACE2/Angiotensin-(1–7)/MAS Axis of the Renin-Angiotensin System: Focus on Angiotensin-(1–7)

Robson Augusto Souza Santos, Walkyria Oliveira Sampaio, Andreia C. Alzamora et al.

Physiological Reviews 2018 10.1152/physrev.00023.2016

[11]

Paz Ocaranza "Counter-regulatory renin-angiotensin system in cardiovascular disease" Nat. Rev. Cardiol. (2020) 10.1038/s41569-019-0244-8

[12]

Alenina "ACE2 in Brain Physiology and Pathophysiology: Evidence from Transgenic Animal Models" Neurochem. Res. (2019) 10.1007/s11064-018-2679-4

[13]

Gheblawi "Angiotensin-Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System: Celebrating the 20th Anniversary of the Discovery of ACE2" Circ. Res. (2020) 10.1161/circresaha.120.317015

[14]

Zhang "Collectrin, a collecting duct-specific transmembrane glycoprotein, is a novel homolog of ACE2 and is developmentally regulated in embryonic kidneys" J. Biol. Chem. (2001) 10.1074/jbc.m006723200

[15]

Singer "Collectrin and ACE2 in renal and intestinal amino acid transport" Channels (Austin) (2011) 10.4161/chan.5.5.16470

[16]

Danilczyk "Essential role for collectrin in renal amino acid transport" Nature (2006) 10.1038/nature05475

[17]

Jarajapu "Targeting ACE2/Angiotensin-(1-7)/Mas Receptor Axis in the Vascular Progenitor Cells for Cardiovascular Diseases" Mol. Pharmacol. (2020) 10.1124/mol.119.117580

[18]

Jarajapu "Activation of the ACE2/angiotensin-(1-7)/Mas receptor axis enhances the reparative function of dysfunctional diabetic endothelial progenitors" Diabetes (2013) 10.2337/db12-0808

[19]

Mendoza-Torres "ACE2 and vasoactive peptides: novel players in cardiovascular/renal remodeling and hypertension" Ther. Adv. Cardiovasc. Dis. (2015) 10.1177/1753944715597623

[20]

Role of the ACE2/Angiotensin 1–7 Axis of the Renin–Angiotensin System in Heart Failure

Vaibhav B. Patel, Jiu-Chang Zhong, Maria B. Grant et al.

Circulation Research 2016 10.1161/circresaha.116.307708

[21]

Kuba "Angiotensin-converting enzyme 2 in lung diseases" Curr. Opin. Pharmacol. (2006) 10.1016/j.coph.2006.03.001

[22]

Jia "Pulmonary Angiotensin-Converting Enzyme 2 (ACE2) and Inflammatory Lung Disease" Shock (2016) 10.1097/shk.0000000000000633

[23]

Rein "Renin-Angiotensin System in Diabetes" Protein Pept. Lett. (2017) 10.2174/0929866524666170728144357

[24]

Obukhov "SARS-CoV-2 Infections and ACE2: Clinical Outcomes Linked With Increased Morbidity and Mortality in Individuals With Diabetes" Diabetes (2020) 10.2337/dbi20-0019

[25]

Crowley "Immunologic Effects of the Renin-Angiotensin System" J. Am. Soc. Nephrol. (2017) 10.1681/asn.2016101066

[26]

Brzozowski "Role of renin-angiotensin system and metabolites of angiotensin in the mechanism of gastric mucosal protection" Curr. Opin. Pharmacol. (2014) 10.1016/j.coph.2014.08.007

[27]

Cole-Jeffrey "ACE2 and Microbiota: Emerging Targets for Cardiopulmonary Disease Therapy" J. Cardiovasc. Pharmacol. (2015) 10.1097/fjc.0000000000000307

[28]

Perlot "ACE2 - from the renin-angiotensin system to gut microbiota and malnutrition" Microbes Infect. (2013) 10.1016/j.micinf.2013.08.003

[29]

Andrade "The Angiotensin Converting Enzyme 2 (ACE2), Gut Microbiota, and Cardiovascular Health" Protein Pept Lett. (2017)

[30]

Huentelman "Protection from angiotensin II-induced cardiac hypertrophy and fibrosis by systemic lentiviral delivery of ACE2 in rats" Exp. Physiol. (2005) 10.1113/expphysiol.2005.031096

[31]

Diez-Freire "ACE2 gene transfer attenuates hypertension-linked pathophysiological changes in the SHR" Physiol. Genomics (2006) 10.1152/physiolgenomics.00312.2005

[32]

Der Sarkissian "Cardiac overexpression of angiotensin converting enzyme 2 protects the heart from ischemia-induced pathophysiology" Hypertension (2008) 10.1161/hypertensionaha.107.100693

[33]

Yamazato "Overexpression of angiotensin-converting enzyme 2 in the rostral ventrolateral medulla causes long-term decrease in blood pressure in the spontaneously hypertensive rats" Hypertension (2007) 10.1161/01.hyp.0000259942.38108.20

[34]

Li "Angiotensin-converting enzyme 2 prevents lipopolysaccharide-induced rat acute lung injury via suppressing the ERK1/2 and NF-kappaB signaling pathways" Sci. Rep. (2016) 10.1038/srep27911

[35]

Shenoy "The angiotensin-converting enzyme 2/angiogenesis-(1-7)/Mas axis confers cardiopulmonary protection against lung fibrosis and pulmonary hypertension" Am. J. Respir. Crit. Care Med. (2010) 10.1164/rccm.200912-1840oc

[36]

Yamazato "Prevention of pulmonary hypertension by Angiotensin-converting enzyme 2 gene transfer" Hypertension (2009) 10.1161/hypertensionaha.108.125468

[37]

Meng "The angiotensin-converting enzyme 2/angiotensin (1-7)/Mas axis protects against lung fibroblast migration and lung fibrosis by inhibiting the NOX4-derived ROS-mediated RhoA/Rho kinase pathway" Antioxid. Redox. Signal. (2015) 10.1089/ars.2013.5818

[38]

Chodavarapu "High-fat diet-induced glucose dysregulation is independent of changes in islet ACE2 in mice" Am. J. Physiol. Regul. Integr. Comp. Physiol. (2016) 10.1152/ajpregu.00362.2016

[39]

Bindom "Angiotensin I-converting enzyme type 2 (ACE2) gene therapy improves glycemic control in diabetic mice" Diabetes (2010) 10.2337/db09-0782

[40]

Chhabra "Pancreatic angiotensin-converting enzyme 2 improves glycemia in angiotensin II-infused mice" Am. J. Physiol. Endocrinol. Metab. (2013) 10.1152/ajpendo.00490.2012

[41]

Dong "Angiotensin-converting enzyme-2 overexpression improves left ventricular remodeling and function in a rat model of diabetic cardiomyopathy" J. Am. Coll. Cardiol. (2012) 10.1016/j.jacc.2011.09.071

[42]

Zhao "ACE2 overexpression ameliorates left ventricular remodeling and dysfunction in a rat model of myocardial infarction" Hum. Gene Ther. (2010) 10.1089/hum.2009.160

[43]

Ma "Angiotensin-converting enzyme 2 overexpression protects against doxorubicin-induced cardiomyopathy by multiple mechanisms in rats" Oncotarget (2017) 10.18632/oncotarget.15595

[44]

Kikuchi "Targeted modification of atrial electrophysiology by homogeneous transmural atrial gene transfer" Circulation (2005) 10.1161/01.cir.0000153338.47507.83

[45]

Fan "Atrial overexpression of angiotensin-converting enzyme 2 improves the canine rapid atrial pacing-induced structural and electrical remodeling. Fan, ACE2 improves atrial substrate remodeling" Basic Res. Cardiol. (2015) 10.1007/s00395-015-0499-0

[46]

Zhou "Angiotensin-converting enzyme-2 overexpression improves atrial remodeling and function in a canine model of atrial fibrillation" J. Am. Heart Assoc. (2015) 10.1161/jaha.114.001530

[47]

Zhou "Angiotensin-converting enzyme-2 overexpression improves atrial electrical remodeling through TRPM7 signaling pathway" Oncotarget (2017) 10.18632/oncotarget.20221

[48]

Sriramula "ACE2 overexpression in the paraventricular nucleus attenuates angiotensin II-induced hypertension" Cardiovasc. Res. (2011) 10.1093/cvr/cvr242

[49]

Xia "ACE2-mediated reduction of oxidative stress in the central nervous system is associated with improvement of autonomic function" PLoS One (2011) 10.1371/journal.pone.0022682

[50]

Zheng "Angiotensin-converting enzyme 2 overexpression improves central nitric oxide-mediated sympathetic outflow in chronic heart failure" Am. J. Physiol. Heart Circ. Physiol. (2011) 10.1152/ajpheart.00330.2011

Showing 50 of 176 references

Cited By

13

Research Progress of Food-Derived Antihypertensive Peptides in Regulating the Key Factors of the Renin–Angiotensin System

Xinyu Yao, Xinyi Cao · 2024

Nutrients

Metrics

13

Citations

176

References

Details

Published: Oct 01, 2020
Vol/Issue: 134(19)
Pages: 2581-2595

Authors

Q

Qiuhong Li

Department of Ophthalmology, University of Florida College of Medicine, Gainesville, FL, U.S.A.

M

Maria B. Grant

Department of Ophthalmology and Visual Sciences, University of Alabama College of Medicine, Birmingham, AL, U.S.A.

E

Elaine M. Richards

Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, FL, U.S.A.

M

Mohan K. Raizada

Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, FL, U.S.A.

Cite This Article

Qiuhong Li, Maria B. Grant, Elaine M. Richards, et al. (2020). ACE2 as therapeutic agent. Clinical Science, 134(19), 2581-2595. https://doi.org/10.1042/cs20200570

ACE2 as therapeutic agent

You May Also Like