key: cord-0698495-p48swqzy authors: Kaur, Upinder; Acharya, Kumudini; Mondal, Ritwick; Singh, Amit; Saso, Luciano; Chakrabarti, Sasanka; Chakrabarti, Sankha Shubhra title: Should ACE2 be given a chance in COVID-19 therapeutics: A semi-systematic review of strategies enhancing ACE2 date: 2020-09-11 journal: Eur J Pharmacol DOI: 10.1016/j.ejphar.2020.173545 sha: 37eac3e242e39ab0cb36c8e4a7bf4f65ffd7499a doc_id: 698495 cord_uid: p48swqzy The severe acute respiratory syndrome corona virus-2 (SARS-CoV-2) has resulted in almost 18 million cases of COVID-19 (Corona virus disease-2019) and more than 670000 deaths worldwide since December 2019. In the absence of effective antiviral therapy and vaccine, treatment of COVID-19 is largely symptomatic. By making use of its spike (S) protein, the virus binds to its primary human cell receptor, angiotensin converting enzyme 2 (ACE2) which is present in the pulmonary epithelial cells as well as other organs. SARS-CoV-2 may cause a downregulation of ACE2. ACE2 plays a protective role in the pulmonary system through its Mas-receptor and alamandine-MrgD-TGR7 pathways. Loss of this protective effect could be a major component of COVID-19 pathogenesis. An attractive strategy in SARS-CoV-2 therapeutics would be to augment ACE2 either directly by supplementation or indirectly through drugs which increase its levels or stimulate its downstream players. In this semi-systematic review, we have analysed the pathophysiological interplay between ACE and ACE2 in the cardiopulmonary system, the modulation of these two proteins by SARS-CoV-2, and potential therapeutic avenues targeting ACE-Ang II and ACE2-Ang (1–7) axes, that can be utilized against COVID-19 disease progression. hydrochlorothiazide has been seen to reduce plasma Ang II/Ang I ratio and 10 plasma ACE in SHR strains. In normotensive and non-SHR rats, 11 hydrochlorothiazide increases cardiac ACE2. No difference was however 12 observed in cardiac angiotensin-AT 1 and Mas-receptor expression between SHR 13 and normotensive rats following hydrochlorothiazide treatment (Jessup et al., 14 2008 ). The new drug valsartan-sacubitril combination, compared to valsartan 15 alone, has shown better results with respect to blood pressure lowering and 16 cardiac upregulation of ACE2 and angiotensin-AT 2 receptor mRNA in SHRs 17 Hyperglycaemia is known to augment the RAAS axis. In turn, the latter through 2 unopposed Ang II and suppressed Ang (1-7) pathway contributes to the database study of SARS-CoV patients observed hyperglycaemia in as high as 10 50% patients in the absence of previous history of diabetes, chronic liver or 11 kidney disease and steroid use. Since ACE2 is expressed on pancreatic beta 12 cells, the authors proposed SARS mediated direct beta cell dysfunction as a 13 probable cause of the new onset diabetes (Yang et al., 2010) . Viral stress 14 mediated hypothalamic-pituitary activation and cortisol production also leads to 15 elevated blood sugar levels necessitating the need for anti-diabetic medications. 16 We therefore performed a search for antidiabetic therapies that can possibly 17 modulate the RAAS/ACE2 arms. The drug also improved cardiac fibrosis, increased Ang (1-7) and ACE2 and 12 reduced ACE/ACE2 ratio in the heart in an animal model of streptozotocin 13 induced diabetes (Qiao et al., 2015) . 14 6.4.2. Insulin-Insulin administration has also been shown to reduce urinary 15 ACE2, renal ADAM-17 and renal ACE2 in various mouse models of type-1 16 diabetes (Riera et al., 2014; Salem et al., 2014) . Insulin has additional 17 immunomodulatory and anti-inflammatory roles such as blunting NF-Kβ 18 signalling, reducing the levels of TNF-α and interfering with neutrophil 6.4.3. Drugs acting through GLP-1 receptor-Liraglutide, a glucagon-like 1 peptide-1 (GLP-1) agonist which is approved for both diabetes and obesity, was 2 found to improve lung development in pups of food deprived mother rats via Resveratrol has been found to increase ACE2 and reduce the development of 21 abdominal aortic aneurysm in APOE knock out mice exposed to HFD and Ang 1 II infusion (Moran et al., 2017) . Sirtuin-6 attenuates Ang II mediated cardiac 2 fibrosis in rats by activating AMP kinase and the ACE2 pathway (Zhang et al., 3 2017 ). This may also explain lower mortality trends observed in female patients of 7 COVID-19 compared to males. /Mas Receptor Is a Possible Strategy to Treat Coronavirus Focus on Receptors for 8 as a Potential Drug Target -A Perspective Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes Estradiol, acting through ERα, induces endothelial non-classic renin-3 angiotensin system increasing angiotensin 1-7 production Inhibition of SARS-CoV-2 Infections Engineered Human Tissues Using Clinical-Grade Soluble Human ACE2 Original Research: ACE2 activator associated with physical exercise 5 potentiates the reduction of pulmonary fibrosis The potential actions of 10 angiotensin-converting enzyme II (ACE2) activator diminazene aceturate 11 (DIZE) in various diseases Ibuprofen Attenuates Cardiac Fibrosis in Reverses Angiotensin-Converting Enzyme-2 Inhibition and Decreases ACE2 Activity and Kidney Function in the Non-Obese Diabetic Mouse To protect peptide pharmaceuticals 13 against peptidases infection par le COVID-19 : vraiment ? ADAM17 and ACE2 shedding in diabetic Akita mice a Ligand to PPAR γ Improves Blood Pressure and Vascular Function through Renin 5203-Porcine Model: Possible Role of the Renin-Angiotensin System Protective effect and mechanism of β-CM7 on renin angiotensin system & 5 diabetic cardiomyopathy Effect of Astragali Radix in improving early renal 8 damage in metabolic syndrome rats through ACE2/Mas pathway Cardioprotective Effects of Qishenyiqi Mediated by Angiotensin 12 II Type 1 Receptor Blockade and Enhancing Angiotensin-Converting Enzyme 2. Evidence-Based Complement Enzyme 2 Gene Expression Levels in Cultured Neonatal Rat Apelin/APJ system: an emerging 5 therapeutic target for respiratory diseases Binding of SARS 8 coronavirus to its receptor damages islets and causes acute diabetes Liraglutide 11 Attenuates Non-Alcoholic Fatty Liver Disease in Mice by Regulating the Zhongguo Zhong xi yi jie he za zhi Zhongguo Zhongxiyi jiehe zazhi = Peptide-1 Level Attenuates Angiotensin II-Induced Tissue Fibrosis by Altering AT1/AT2 Receptor Expression and Angiotensin-Converting Enzyme 2 Activity in Rat Heart Upregulation of Angiotensin-Converting Enzyme 2 by All