Pharmacotherapy in COVID-19 patients: a review of ACE2-raising drugs and their clinical safety

References

• Bourgonje AR, Abdulle AE, Timens W, et al. Angiotensin-converting enzyme 2 (ACE2), SARS-CoV-2 and the pathophysiology of coronavirus disease 2019 (COVID-19). J Pathol. 2020;251(3):228–248.
   PubMed Web of Science ®Google Scholar
• Guan WJ, Ni ZY, Hu Y, Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020;382(18):1708–1720.
   PubMed Web of Science ®Google Scholar
• Wu C, Chen X, Cai Y, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med. 2020a;180(7):934.
   PubMed Web of Science ®Google Scholar
• Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054–1062.
   PubMed Web of Science ®Google Scholar
• Donoghue M, Hsieh F, Baronas E, et al. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ Res. 2000;87(5):e1–e9.
   PubMed Web of Science ®Google Scholar
• Tipnis SR, Hooper NM, Hyde R, et al. A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase. J Biol Chem. 2000;275(43):33238–33243.
   PubMed Web of Science ®Google Scholar
• Xu H, Zhong L, Deng J, et al. High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa. Int J Oral Sci. 2020;12. DOI:10.1038/s41368-020-0074-x
   Web of Science ®Google Scholar
• Hamming I, Timens W, Bulthuis ML, et al. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004;203(2):631–637.
   PubMed Web of Science ®Google Scholar
• Bunyavanich S, Do A, Vicencio A. Nasal gene expression of angiotensin-converting enzyme 2 in children and adults. JAMA. 2020;323(23):2427.
   PubMed Web of Science ®Google Scholar
• Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020;181(2):271–280.e8.
   Google Scholar
• Yan R, Zhang Y, Li Y, et al. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science. 2020;367(6485):1444–1448.
   PubMed Web of Science ®Google Scholar
• Varga Z, Flammer AJ, Steiger P, et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet. 2020;395:1417–1418.
   PubMed Web of Science ®Google Scholar
• Kuba K, Imai Y, Rao S, et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med. 2005;11(8):875–879.
   PubMed Web of Science ®Google Scholar
• Tai W, He L, Zhang X, et al. Characterization of the receptor-binding domain (RBD) of 2019 novel coronavirus: Implication for development of RBD protein as a viral attachment inhibitor and vaccine. Cell Mol. Immunol. 2020;17:613–620.
   PubMed Web of Science ®Google Scholar
• Wrapp D, Wang N, Corbett KS, et al. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science. 2020;367(6483):1260–1263.
   PubMed Web of Science ®Google Scholar
• Lambert DW, Yarski M, Warner FJ, et al. Tumor necrosis factor-alpha convertase (ADAM17) mediates regulated ectodomain shedding of the severe-acute respiratory syndrome-coronavirus (SARS-CoV) receptor, angiotensin-converting enzyme-2 (ACE2). J Biol Chem. 2005;280(34):30113–30119.
   PubMed Web of Science ®Google Scholar
• Oudit GY, Pfeffer MA. Plasma angiotensin-converting enzyme 2: novel biomarker in heart failure with implications for COVID-19. Eur Heart J. 2020;41(19):1818–1820.
   PubMed Web of Science ®Google Scholar
• South AM, Diz DI, Chappell MC. COVID-19, ACE2, and the cardiovascular consequences. Am J Physiol Heart Circ Physiol. 2020;318(5):H1084–H1090.
   PubMed Web of Science ®Google Scholar
• Gheblawi M, Wang K, Viveiros A, et al. Angiotensin converting enzyme 2: SARS-CoV-2 receptor and regulator of the renin-angiotensin system. Circ Res. 2020;126(10):1456–1474.
   PubMed Web of Science ®Google Scholar
• Santos RAS, Oudit GY, Verano-Braga T, et al. The renin-angiotensin system: going beyond the classical paradigms. Am J Physiol Heart Circ Physiol. 2019;316(5):H958–H970.
   PubMed Web of Science ®Google Scholar
• Yousif MHM, Makki B, El-Hashim AZ, et al. Chronic treatment with Ang-(1-7) reverses abnormal reactivity in the corpus cavernosum and normalizes diabetes-induced changes in the protein levels of ACE, ACE2, ROCK1, ROCK2 and omega-hydroxylase in a rat model of type 1 diabetes. J Diabetes Res. 2014;2014:142154.
   PubMed Web of Science ®Google Scholar
• Devaux CA, Rolain JM, Raoult D. ACE2 receptor polymorphism: Susceptibility to SARS-CoV-2, hypertension, multi-organ failure, and COVID-19 disease outcome. J Microbiol Immunol Infect. 2020;53(3):425–435.
   PubMedGoogle Scholar
• Ferrario CM, Ahmad S, Joyner J, et al. Advances in the renin angiotensin system focus on angiotensin-converting enzyme 2 and angiotensin-(1-7). Adv Pharmacol. 2010;59:197–233.
   PubMedGoogle Scholar
• Paz Ocaranza M, Riquelme JA, García L, et al. Counter-regulatory renin-angiotensin system in cardiovascular disease. Nat Rev Cardiol. 2020;17(2):116–129.
   PubMedGoogle Scholar
• Re RN. Role of intracellular angiotensin II. Am J Physiol Heart Circ Physiol. 2018;314(4):H766–H771.
   PubMed Web of Science ®Google Scholar
• Ferrario CM. Role of angiotensin II in cardiovascular disease therapeutic implications of more than a century of research. J Renin Angiotensin Aldosterone Syst. 2006;7(1):3–14.
   PubMed Web of Science ®Google Scholar
• El-Hashim AZ, Renno WM, Raghupathy R, et al. Angiotensin-(1-7) inhibits allergic inflammation, via the MAS1 receptor, through suppression of ERK1/2- and NF-κB-dependent pathways. Br J Pharmacol. 2012; 166(6):1964–1976.
   PubMed Web of Science ®Google Scholar
• Arendse LB, Danser AHJ, Poglitsch M, et al. Novel therapeutic approaches targeting the renin-angiotensin system and associated peptides in hypertension and heart failure. Pharmacol Rev. 2019;71(4):539–570.
   PubMed Web of Science ®Google Scholar
• Benter IF, Diz DI, Ferrario CM. Cardiovascular actions of angiotensin(1-7). Peptides. 1993;14(4):679–684.
   PubMed Web of Science ®Google Scholar
• Benter IF, Ferrario CM, Morris M, et al. Antihypertensive actions of angiotensin-(1-7) in spontaneously hypertensive rats. Am J Physiol. 1995;269(1 Pt 2):H313–H319.
   PubMedGoogle Scholar
• Benter IF, Diz DI, Ferrario CM. Pressor and reflex sensitivity is altered in spontaneously hypertensive rats treated with angiotensin-(1-7). Hypertension. 1995;26(6):1138–1144.
   PubMed Web of Science ®Google Scholar
• Al-Maghrebi M, Benter IF, Diz DI. Endogenous angiotensin-(1-7) reduces cardiac ischemia-induced dysfunction in diabetic hypertensive rats. Pharmacol Res. 2009;59(4):263–268.
   PubMed Web of Science ®Google Scholar
• Benter IF, Yousif MH, Dhaunsi GS, et al. Angiotensin-(1-7) prevents activation of NADPH oxidase and renal vascular dysfunction in diabetic hypertensive rats. Am J Nephrol. 2008;28(1):25–33.
   PubMed Web of Science ®Google Scholar
• Dhaunsi GS, Yousif MH, Akhtar S, et al. Angiotensin-(1-7) prevents diabetes-induced attenuation in PPAR-gamma and catalase activities. Eur J Pharmacol. 2010; 638(1–3):108–114.
   PubMed Web of Science ®Google Scholar
• Tallant EA, Diz DI, Ferrario CM. State-of-the-art lecture. Antiproliferative actions of angiotensin-(1-7) in vascular smooth muscle. Hypertension. 1999;34(4 Pt 2):950–957. Oct
   PubMed Web of Science ®Google Scholar
• Benter IF, Yousif MH, Anim JT, et al. Angiotensin-(1-7) prevents development of severe hypertension and end-organ damage in spontaneously hypertensive rats treated with L-NAME. Am J Physiol Heart Circ Physiol. 2006;290(2):H684–H691.
   PubMed Web of Science ®Google Scholar
• Benter IF, Yousif MH, Cojocel C, et al. Angiotensin-(1-7) prevents diabetes-induced cardiovascular dysfunction. Am J Physiol Heart Circ Physiol. 2007;292(1):H666–H672.
   PubMed Web of Science ®Google Scholar
• Cao Y, Liu Y, Shang J, et al. Ang-(1-7) treatment attenuates lipopolysaccharide-induced early pulmonary fibrosis. Lab Invest. 2019;99(12):1770–1783.
   PubMed Web of Science ®Google Scholar
• Magalhães GS, Gregório JF, Ramos KE, et al. Treatment with inhaled formulation of angiotensin-(1-7) reverses inflammation and pulmonary remodeling in a model of chronic asthma. Immunobiology. 2020;225(3):151957. PMID: 32517880
   PubMed Web of Science ®Google Scholar
• Benter IF, Yousif MH, Al-Saleh FM, et al. Angiotensin-(1-7) blockade attenuates captopril- or hydralazine-induced cardiovascular protection in spontaneously hypertensive rats treated with NG-nitro-L-arginine methyl ester. J Cardiovasc Pharmacol. 2011;57(5):559–567.
   PubMed Web of Science ®Google Scholar
• Ishiyama Y, Gallagher PE, Averill DB, Tallant EA, et al. Upregulation of angiotensin-converting enzyme 2 after myocardial infarction by blockade of angiotensin II receptors. Hypertension. 2004;43(5):970–976.
   PubMed Web of Science ®Google Scholar
• Dijkman R, Jebbink MF, Deijs M, et al. Replication-dependent downregulation of cellular angiotensin-converting enzyme 2 protein expression by human coronavirus NL63. J Gen Virol. 2012;93(Pt 9):1924–1929.
   PubMedGoogle Scholar
• Li W, Moore MJ, Vasilieva N, et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature. 2003;426(6965):450–454.
   PubMed Web of Science ®Google Scholar
• Ingraham NE, Barakat AG, Reilkoff R, et al. Understanding the renin-angiotensin-aldosterone-SARS-CoV axis: a comprehensive review. Eur Respir J. 2020;56(1):2000912.
   PubMed Web of Science ®Google Scholar
• Ye R, Liu Z. ACE2 exhibits protective effects against LPS-induced acute lung injury in mice by inhibiting the LPS-TLR4 pathway. Exp Mol Pathol. 2020;113:104350
   PubMed Web of Science ®Google Scholar
• Gu H, Xie Z, Li T, et al. Angiotensin-converting enzyme 2 inhibits lung injury induced by respiratory syncytial virus. Sci Rep. 2016;6:19840
   PubMed Web of Science ®Google Scholar
• Imai Y, Kuba K, Rao S, et al. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature. 2005;436(7047):112–116.
   PubMed Web of Science ®Google Scholar
• Mazucanti CH, Egan JM. SARS-CoV-2 disease severity and diabetes: why the connection and what is to be done? Immun Ageing. 2020; 17:21.
   PubMed Web of Science ®Google Scholar
• Ferrario CM, Jessup J, Chappell MC, et al. Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2. Circulation. 2005a;111(20):2605–2610.
   PubMed Web of Science ®Google Scholar
• Jessup JA, Gallagher PE, Averill DB, Brosnihan KB, et al. Effect of angiotensin ii blockade on a new congenic model of hypertension derived from transgenic ren-2 rats. Am J Physiol Heart Circ Physiol. 2006;291(5):H2166–2172.
   PubMed Web of Science ®Google Scholar
• Patel VB, Clarke N, Wang Z, et al. Angiotensin ii induced proteolytic cleavage of myocardial ace2 is mediated by tace/adam-17: a positive feedback mechanism in the ras. J Mol Cell Cardiol. 2014;66:167–176.
   PubMed Web of Science ®Google Scholar
• Jin HY, Song B, Oudit GY, et al. Ace2 deficiency enhances angiotensin ii-mediated aortic profilin-1 expression, inflammation and peroxynitrite production. PLoS One. 2012;7(6):e38502.
   PubMed Web of Science ®Google Scholar
• Soler MJ, Ye M, Wysocki J, et al. Localization of ace2 in the renal vasculature: amplification by angiotensin II type 1 receptor blockade using telmisartan. Am J Physiol Renal Physiol. 2009;296(2):F398–F405.
   PubMed Web of Science ®Google Scholar
• Igase M, Strawn WB, Gallagher PE, et al. Angiotensin ii at1 receptors regulate ace2 and angiotensin-(1-7) expression in the aorta of spontaneously hypertensive rats. Am J Physiol Heart Circ Physiol. 2005;289(3):H1013–H1019.
   PubMed Web of Science ®Google Scholar
• Furuhashi M, Moniwa N, Mita T, et al. Urinary angiotensin-converting enzyme 2 in hypertensive patients may be increased by olmesartan, an angiotensin II receptor blocker. Am J Hypertens. 2015;28(1):15–21.
   PubMed Web of Science ®Google Scholar
• Ocaranza MP, Godoy I, Jalil JE, et al. Enalapril attenuates downregulation of Angiotensin-converting enzyme 2 in the late phase of ventricular dysfunction in myocardial infarcted rat. Hypertension. 2006;48(4):572–578.
   PubMed Web of Science ®Google Scholar
• Ferrario CM, Jessup J, Gallagher PE, et al. Effects of renin-angiotensin system blockade on renal angiotensin-(1-7) forming enzymes and receptors. Kidney Int. 2005b;68(5):2189–2196.
   PubMed Web of Science ®Google Scholar
• Vuille-dit-Bille RN, Camargo SM, Emmenegger L, et al. Human intestine luminal ACE2 and amino acid transporter expression increased by ACE-inhibitors. Amino Acids. 2015;47(4):693–705.
   PubMed Web of Science ®Google Scholar
• Keidar S, Gamliel-Lazarovich A, Kaplan M, et al. Mineralocorticoid receptor blocker increases angiotensin-converting enzyme 2 activity in congestive heart failure patients. Circ Res. 2005;97(9):946–953.
   PubMed Web of Science ®Google Scholar
• Tikoo K, Patel G, Kumar S, et al. Tissue specific up regulation of ACE2 in rabbit model of atherosclerosis by atorvastatin: role of epigenetic histone modifications. Biochem Pharmacol. 2015;93(3):343–351.
   PubMed Web of Science ®Google Scholar
• Shin YH, Min JJ, Lee JH, et al. The effect of fluvastatin on cardiac fibrosis and angiotensin-converting enzyme-2 expression in glucose-controlled diabetic rat hearts. Heart Vessels. 2017;32(5):618–627.
   PubMed Web of Science ®Google Scholar
• Sánchez-Aguilar M, Ibarra-Lara L, Del Valle-Mondragón L, et al. Rosiglitazone, a ligand to PPARγ, improves blood pressure and vascular function through renin-angiotensin system regulation. PPAR Res. 2019; 2019:1371758.
   PubMed Web of Science ®Google Scholar
• Zhang W, Xu YZ, Liu B, et al. Pioglitazone upregulates angiotensin converting enzyme 2 expression in insulin-sensitive tissues in rats with high-fat diet-induced nonalcoholic steatohepatitis. ScientificWorldJournal. 2014; 2014:603409.
   PubMedGoogle Scholar
• Li Y-H, Wang Q-X, Zhou J-W, et al. Effects of rosuvastatin on expression of angiotensin-converting enzyme 2 after vascular balloon injury in rats. J Geriatr Cardiol. 2013;10(2):151–158.
   PubMedGoogle Scholar
• Romaní-Pérez M, Outeiriño-Iglesias V, Moya CM, et al. Activation of the GLP-1 receptor by liraglutide Increases ACE2 expression, reversing right ventricle hypertrophy, and improving the production of SP-A and SP-B in the lungs of type 1 diabetes rats. Endocrinology. 2015;156(10):3559–3569.
   PubMed Web of Science ®Google Scholar
• Fandiño J, Vaz AA, Toba L, et al. Liraglutide enhances the activity of the ACE-2/Ang(1-7)/Mas receptor pathway in lungs of male pups from food-restricted mothers and prevents the reduction of SP-A. Int J Endocrinol. 2018;2018:6920620.
   PubMedGoogle Scholar
• Zhang L-H, Pang X-F, Bai F, et al. Preservation of glucagon-like peptide-1 level attenuates angiotensin II-induced tissue fibrosis by altering AT1/AT 2 receptor expression and angiotensin-converting enzyme 2 activity in rat heart. Cardiovasc Drugs Ther. 2015;29(3):243–255.
   PubMed Web of Science ®Google Scholar
• Jessup JA, Brosnihan KB, Gallagher PE, et al. Differential effect of low dose thiazides on the renin angiotensin system in genetically hypertensive and normotensive rats. J Am Soc Hypertens. 2008;2(2):106–115.
   PubMed Web of Science ®Google Scholar
• Varagic J, Ahmad S, Voncannon JL, et al. Nebivolol reduces cardiac angiotensin II, associated oxidative stress and fibrosis but not arterial pressure in salt-loaded spontaneously hypertensive rats. J Hypertens. 2012;30(9):1766–1774.
   PubMed Web of Science ®Google Scholar
• Abdel-Fattah MM, Messiha BAS, Mansour AM. Modulation of brain ACE and ACE2 may be a promising protective strategy against cerebral ischemia/reperfusion injury: an experimental trial in rats. Naunyn Schmiedebergs Arch Pharmacol. 2018;391(9):1003–1020.
   PubMed Web of Science ®Google Scholar
• Awwad ZM, El-Ganainy SO, ElMallah AI, et al. Assessment of Pregabalin-Induced Cardiotoxicity in Rats: Mechanistic Role of Angiotensin 1-7. Cardiovasc Toxicol. 2020;20(3):301–311.
   PubMed Web of Science ®Google Scholar
• Qiao W, Wang C, Chen B, et al. Ibuprofen attenuates cardiac fibrosis in streptozotocin-induced diabetic rats. Cardiology. 2015;131(2):97–106.
   PubMed Web of Science ®Google Scholar
• Bukowska A, Spiller L, Wolke C, et al. Protective regulation of the ACE2/ACE gene expression by estrogen in human atrial tissue from elderly men. Exp Biol Med (Maywood)). 2017;242(14):1412–1423.
   PubMed Web of Science ®Google Scholar
• Tanno T, Tomita H, Narita I, et al. Olmesartan Inhibits Cardiac Hypertrophy in Mice Overexpressing Renin Independently of Blood Pressure: Its Beneficial Effects on ACE2/Ang(1-7)/Mas Axis and NADPH Oxidase Expression. J Cardiovasc Pharmacol. 2016;67(6):503–509.
   PubMed Web of Science ®Google Scholar
• Lin M, Gao P, Zhao T, et al. Calcitriol regulates angiotensin-converting enzyme and angiotensin converting-enzyme 2 in diabetic kidney disease. Mol Biol Rep. 2016;43(5):397–406.
   PubMed Web of Science ®Google Scholar
• Wang X, Ye Y, Gong H, et al. The effects of different angiotensin II type 1 receptor blockers on the regulation of the ACE-AngII-AT1 and ACE2-Ang(1-7)-Mas axes in pressure overload-induced cardiac remodeling in male mice. J Mol Cell Cardiol. 2016;97:180–190.
   PubMed Web of Science ®Google Scholar
• Wu C, Ye D, Mullick AE, et al. Effects of renin-angiotensin inhibition on ACE2 and TMPRSS2 expression: insights into COVID-19. bioRxiv. 2020.
   Google Scholar
• Chodavarapu H, Grobe N, Somineni HK, et al. Rosiglitazone treatment of type 2 diabetic db/db mice attenuates urinary albumin and angiotensin converting enzyme 2 excretion. PLoS One. 2013;8(4):e62833.
   PubMed Web of Science ®Google Scholar
• Reimann F, Habib AM, Tolhurst G, et al. Glucose sensing in L cells: a primary cell study. Cell Metab. 2008;8(6):532–539.
   PubMed Web of Science ®Google Scholar
• Habib AM, Richards P, Cairns LS, et al. Overlap of endocrine hormone expression in the mouse intestine revealed by transcriptional profiling and flow cytometry. Endocrinology. 2012;153(7):3054–3065.
   PubMed Web of Science ®Google Scholar
• Habib AM, Richards P, Rogers GJ, et al. Co-localisation and secretion of glucagon-like peptide 1 and peptide YY from primary cultured human L cells. Diabetologia. 2013;56(6):1413–1416.
   PubMed Web of Science ®Google Scholar
• Gribble FM, Reimann F. Enteroendocrine cells: chemosensors in the intestinal epithelium. Annu Rev Physiol. 2016;78:277–299.
   PubMed Web of Science ®Google Scholar
• Gribble FM, Reimann F. Function and mechanisms of enteroendocrine cells and gut hormones in metabolism. Nat Rev Endocrinol. 2019;15(4):226–237.
   PubMed Web of Science ®Google Scholar
• Pais R, Rievaj J, Larraufie P, et al. Angiotensin II Type 1 receptor-dependent GLP-1 and PYY secretion in mice and humans. Endocrinology. 2016;157(10):3821–3831.
   PubMed Web of Science ®Google Scholar
• McCormack FX, Whitsett JA. The pulmonary collectins, SP-A and SP-D, orchestrate innate immunity in the lung. J Clin Invest. 2002;109(6):707–712.
   PubMed Web of Science ®Google Scholar
• Lely AT, Hamming I, van Goor H, et al. Renal ACE2 expression in human kidney disease. J Pathol. 2004;204(5):587–593.
   PubMed Web of Science ®Google Scholar
• Epelman S, Shrestha K, Troughton RW, et al. Soluble angiotensin-converting enzyme 2 in human heart failure: relation with myocardial function and clinical outcomes. J Card Fail. 2009;15(7):565–571.
   PubMed Web of Science ®Google Scholar
• Walters TE, Kalman JM, Patel SK, et al. Angiotensin converting enzyme 2 activity and human atrial fibrillation: increased plasma angiotensin converting enzyme 2 activity is associated with atrial fibrillation and more advanced left atrial structural remodelling. Europace. 2017;19:1280–1287.
   PubMed Web of Science ®Google Scholar
• Ramchand J, Patel SK, Kearney LG, et al. Plasma ACE2 activity predicts mortality in aortic stenosis and is associated with severe myocardial fibrosis. JACC Cardiovasc Imaging. 2020;13(3):655–664.
   PubMed Web of Science ®Google Scholar
• Ramchand J, Patel SK, Srivastava PM, et al. Elevated plasma angiotensin converting enzyme 2 activity is an independent predictor of major adverse cardiac events in patients with obstructive coronary artery disease. PLoS One. 2018;13(6):e0198144.
   PubMed Web of Science ®Google Scholar
• Luque M, Martin P, Martell N, et al. Effects of captopril related to increased levels of prostacyclin and angiotensin-(1-7) in essential hypertension. J Hypertens. 1996;14(6):799–805.
   PubMed Web of Science ®Google Scholar
• Campbell DJ, Zeitz CJ, Esler MD, et al. Evidence against a major role for angiotensin converting enzyme-related carboxypeptidase (ACE2) in angiotensin peptide metabolism in the human coronary circulation. J Hypertens. 2004;22:1971–1976.
   PubMed Web of Science ®Google Scholar
• Vaduganathan M, Vardeny O, Michel T, et al. Renin-angiotensin-aldosterone system inhibitors in patients with Covid-19. N Engl J Med. 2020;382(17):1653–1659.
   PubMed Web of Science ®Google Scholar
• Bader M, Ganten D. Update on tissue renin-angiotensin systems. J Mol Med. 2008;86(6):615–621.
   PubMed Web of Science ®Google Scholar
• Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir Med. 2020;8(4):e21.
   PubMed Web of Science ®Google Scholar
• Sommerstein R, Kochen MM, Messerli FH, GräNi C. Coronavirus Disease 2019 (COVID-19): do angiotensin-converting enzyme inhibitors/angiotensin receptor blockers have a biphasic effect? J Am Heart Assoc. 2020;9(7):e016509.
   PubMed Web of Science ®Google Scholar
• Hanff TC, Harhay MO, Brown TS, et al. Is there an association between COVID-19 mortality and the renin-angiotensin system-a call for epidemiologic investigations. Clin Infect Dis. 2020;71(15):870–4.
   PubMed Web of Science ®Google Scholar
• Sommerstein R. Re: Preventing a COVID-19 pandemic: ACE inhibitors as a potential risk factor for fatal COVID-19. BMJ. 2020;368:m810. DOI:10.1136/bmj.m810
   Google Scholar
• Wu Z, McGoogan JM. Characte
   Google Scholar
  ristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention. JAMA. 2020;323(13):1239.
   PubMed Web of Science ®Google Scholar
• Huang Z, Cao J, Yao Y, et al. The effect of RAS blockers on the clinical characteristics of COVID-19 patients with hypertension. Ann Transl Med. 2020;8(7):430.
   PubMed Web of Science ®Google Scholar
• Guo T, Fan Y, Chen M, et al. Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19). JAMA Cardiol. 2020;5(7):811.
   PubMed Web of Science ®Google Scholar
• Gurwitz D. Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics. Drug Dev Res. 2020. DOI:ddr.21656/ddr.21656. [Online ahead of print].
   Web of Science ®Google Scholar
• Patel AB, Verma A. COVID-19 and angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: what is the evidence? JAMA. 2020. DOI:10.1001/jama.2020.4812. [Online ahead of print].
   Web of Science ®Google Scholar
• Mourad JJ, Levy BI. Interaction between RAAS inhibitors and ACE2 in the context of COVID-19. Nat Rev Cardiol. 2020;17(5):313.
   PubMed Web of Science ®Google Scholar
• Monteil V, Kwon H, Prado P, et al. Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2. Cell. 2020;181(4):905.e7–913.e7.
   Web of Science ®Google Scholar
• Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;579(7798):270–273.
   PubMed Web of Science ®Google Scholar
• Liu Y, Huang F, Xu J, et al. Anti-hypertensive angiotensin II receptor blockers associated to mitigation of disease severity in elderly COVID-19 patients. 2020 [Posted 2020 Mar 27].
   Google Scholar
• Mancia G, Rea F, Ludergnani M, et al. Renin-Angiotensin-Aldosterone System Blockers and the Risk of Covid-19. N Engl J Med. 2020;382(25):2431–2440.
   PubMed Web of Science ®Google Scholar
• Reynolds HR, Adhikari S, Pulgarin C, et al. Renin-Angiotensin-Aldosterone System Inhibitors and Risk of Covid-19. N Engl J Med. 2020;18382(25):2441–2448.
   PubMed Web of Science ®Google Scholar
• Yang G, Tan Z, Zhou L, et al. Effects of ARBs and ACEIs on virus infection, inflammatory status and clinical outcomes In COVID-19 patients with hypertension: a single center retrospective study. Hypertension. 2020;76(1):51–58.
   PubMed Web of Science ®Google Scholar
• Feng Z, Li J, Yao S, et al. The use of adjuvant therapy in preventing progression to severe pneumonia in patients with coronavirus disease 2019: a multicenter data analysis. 2020. DOI:10.1101/2020.04.08.20057539
   Google Scholar
• Li J, Wang X, Chen J, et al. Association of renin-angiotensin system inhibitors with severity or risk of death in patients with hypertension hospitalized for coronavirus disease 2019 (COVID-19) Infection in Wuhan, China. JAMA Cardiol. 2020;5(7):825.
   PubMed Web of Science ®Google Scholar
• Meng J, Xiao G, Zhang J, et al. Renin-angiotensin system inhibitors improve the clinical outcomes of COVID-19 patients with hypertension. Emerg Microbes Infect. 2020;9(1):757–760.
   PubMed Web of Science ®Google Scholar
• de Abajo FJ, Rodríguez-Martín S, Lerma V, MED-ACE2-COVID19 study group, et al. Use of renin-angiotensin-aldosterone system inhibitors and risk of COVID-19 requiring admission to hospital: a case-population study. Lancet. 2020;395(10238):1705–1714.
   PubMed Web of Science ®Google Scholar
• Tedeschi S, Giannella M, Bartoletti M, et al. Clinical impact of renin-angiotensin system inhibitors on in-hospital mortality of patients with hypertension hospitalized for Coronavirus Disease 2019. Clin Infect Dis. 2020;71(15):899–901.
   PubMedGoogle Scholar
• Zhang P, Zhu L, Cai J, t al. Association of inpatient use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers with mortality among patients with hypertension hospitalized with COVID-19. Circ Res. 2020b;126(12):1671–1681.
   PubMed Web of Science ®Google Scholar
• Merc Urmes I, et al. Long-term ACE Inhibitor/ARB use is associated with severe renal dysfunction and acute kidney injury in patients with severe COVID-19: results from a referral center cohort in the North East of France. Clin Infect Dis. 2020. DOI:10.1093/cid/ciaa677. [Online ahead of print].
   Google Scholar
• Zhang JJ, Dong X, Cao YY, et al.
   Google Scholar
  Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China. Allergy. 2020a;75(7):1730–1741.
   PubMed Web of Science ®Google Scholar
• Zhang X, Yu J, Pan LY, et al. ACEI/ARB use and risk of infection or severity or mortality of COVID-19: A systematic review and meta-analysis. Pharmacol Res. 2020;158:104927. DOI: 10.1016/j.phrs.2020.104927. PMID: 32422341.
   Google Scholar
• Pirola CJ, Sookoian S. Estimation of Renin-Angiotensin-Aldosterone-System (RAAS)-Inhibitor effect on COVID-19 outcome: A Meta-analysis. J Infect. 2020;28;81(2):276–81.
   Google Scholar
• Mehra MR, Desai SS, Kuy S, et al. Cardiovascular disease, drug therapy, and mortality in Covid-19. N Engl J Med. 2020;382(26):2582–2582.
   PubMed Web of Science ®Google Scholar
• Doi SAR, Barendregt JJ, Khan S, et al. Advances in the meta-analysis of heterogeneous clinical trials I: the inverse variance heterogeneity model. Contemp Clin Trials. 2015;45(Pt A):130–138.
   PubMed Web of Science ®Google Scholar
• Guo W, Li M, Dong Y, et al. Diabetes as a risk factor for the progression and prognosis of COVID-19. Diabetes Metab Res Rev. 2020:e3319.DOI:10.1002/dmrr.3319. [Online ahead of print].
   PubMed Web of Science ®Google Scholar
• Roca-Ho H, Riera M, Palau V, et al. Characterization of ACE and ACE2 expression within different organs of the NOD mouse. IJMS. 2017;18(3):563.
   Google Scholar
• Yousif MHM, Dhaunsi GS, Makki BM, et al. Characterization of Angiotensin-(1-7) effects on the cardiovascular system in an experimental model of type-1 diabetes. Pharmacol Res. 2012;66(3):269–275.
   PubMed Web of Science ®Google Scholar
• Kilarkaje N, Yousif MH, El-Hashim AZ, et al. Role of angiotensin II and angiotensin-(1-7) in diabetes-induced oxidative DNA damage in the corpus cavernosum. Fertil Steril. 2013;100(1):226–233.
   PubMed Web of Science ®Google Scholar
• Dhaunsi GS, Yousif MH, Makki B, et al. Angiotensin-(1-7) downregulates diabetes-induced cGMP phosphodiesterase activation in rat corpus cavernosum. Biomed Res Int. 2017;2017:50849617.
   PubMed Web of Science ®Google Scholar
• Akhtar S, Yousif MH, Dhaunsi GS, et al. Angiotensin-(1-7) inhibits epidermal growth factor receptor transactivation via a Mas receptor-dependent pathway. Br J Pharmacol. 2012;165(5):1390–1400.
   PubMed Web of Science ®Google Scholar
• Akhtar S, Chandrasekhar B, Attur S, et al. Transactivation of ErbB family of receptor tyrosine kinases is inhibited by angiotensin-(1-7) via its mas receptor. PLoS One. 2015;10(11):e0141657.
   PubMed Web of Science ®Google Scholar
• Abwainy A, Babiker FA, Akhtar S, et al. Endogenous Angiotensin-(1-7)/MAS receptor/NO is a novel pathway involved in the cardioprotective effects of pacing postconditioning. Am J Physiol Heart Circ Physiol. 2016;310(1):H104–12.
   Google Scholar
• De Spiegeleer A, Bronselaer A, Teo JT, et al. 2020. The effects of ARBs, ACEIs and statins on clinical outcomes of 2 COVID-19 infection among nursing home residents. J Am Med Dir Assoc. 2020. DOI:10.1016/j.jamda.2020.06.018.
   Google Scholar
• Castiglione V, Chiriacò M, Emdin M, et al. Statin therapy in COVID-19 infection. Eur Heart J Cardiovasc Pharmacother. 2020;6(4):258–259.
   PubMed Web of Science ®Google Scholar
• Jacobson JR, Barnard JW, Grigoryev DN, et al. Simvastatin attenuates vascular leak and inflammation in murine inflammatory lung injury. Am J Physiol Lung Cell Mol Physiol. 2005;288(6):L1026–L1032.
   PubMed Web of Science ®Google Scholar
• Shyamsundar M, McKeown ST, O'Kane CM, et al. Simvastatin decreases lipopolysaccharide-induced pulmonary inflammation in healthy volunteers. Am J Respir Crit Care Med. 2009;179(12):1107–1114.
   PubMed Web of Science ®Google Scholar
• Habib AM, Nagi K, Thillaiappan NB, et al. Vitamin D and Its Potential Interplay With Pain Signaling Pathways. Front Immunol. 2020;11:820
   PubMed Web of Science ®Google Scholar
• Zisi D, Challa A, Makis A. The association between vitamin D status and infectious diseases of the respiratory system in infancy and childhood. Hormones (Athens)). 2019;18(4):353–363.
   PubMedGoogle Scholar
• Hastie CE, Mackay DF, Ho F, et al. Vitamin D concentrations and COVID-19 infection in UK Biobank. Diabetes Metab Syndr. 2020;14(4):561–565.
   PubMed Web of Science ®Google Scholar
• Martineau AR, Jolliffe DA, Hooper RL, et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ (Clinical Research ed.). 2017;356:i6583.
   PubMedGoogle Scholar
• SACN 2020. Rapid review: Vitamin D and acute respiratory tract infections. Published June, 2020 [Accessed 2020 Jul 14]. https://app.box.com/s/g0ldpth1upfd7fw763ew3aqa3c0pyvky.
   Google Scholar
• NICE. COVID-19 rapid evidence summary: vitamin D for COVID-19. 2020 [Published 2020 Jun 29; Accessed 2020 June 14]. https://www.nice.org.uk/advice/es28/resources/covid19-rapid-evidence-summary-vitamin-d-for-covid19-pdf-1158182526661.
   Google Scholar
• Zhuang MW, Cheng Y, Zhang J, et al. Increasing host cellular receptor-angiotensin-converting enzyme 2 (ACE2) expression by coronavirus may facilitate 2019-nCoV (or SARS-CoV-2) Infection. J Med Virol. 2020. DOI:10.1002/jmv.26139. [Online ahead of print].
   Google Scholar
• Riera M, Marquez E, Clotet S, et al. Effect of insulin on ACE2 activity and kidney function in the non-obese diabetic mouse. PloS One. 2014;9(1):e84683.
   PubMed Web of Science ®Google Scholar
• Sardu C, D’Onofrio N, Balestrieri ML, et al. Outcomes in patients with hyperglycemia affected by COVID-19: can we do more on glycemic control. Dia Care. 2020;43(7):1408–1415.
   PubMed Web of Science ®Google Scholar
• RECOVERY Collaborative Group. Effect of Dexamethasone in Hospitalized Patients with COVID-19 – Preliminary Report. medRxiv preprint. 2020.
   Google Scholar
• Ghadhanfar E, Alsalem A, Al-Kandari S, et al. The Role of ACE2, angiotensin-(1-7) and Mas1 receptor axis in glucocorticoid-induced intrauterine growth restriction. Reprod Biol Endocrinol. 2017;15(1):97.
   PubMedGoogle Scholar
• Theoharides TC, Conti P. Dexamethasone for COVID-19? Not so fast. J Biol Regul Homeost Agents. 2020;34(3). DOI:10.23812/20-EDITORIAL_1-5. [Online ahead of print].
   PubMedGoogle Scholar
• Riley RS, June CH, Langer R, et al. Delivery technologies for cancer immunotherapy. Nat Rev Drug Discov. 2019;18(3):175–196.
   PubMed Web of Science ®Google Scholar
• Tibbitt MW, Dahlman JE, Langer R. Emerging frontiers in drug delivery. J Am Chem Soc. 2016;138(3):704–717.
   PubMed Web of Science ®Google Scholar
• Juliano RL. The delivery of therapeutic oligonucleotides. Nucleic Acids Res. 2016;44(14):6518–6548.
   PubMed Web of Science ®Google Scholar
• Ruoslahti E. Tumor penetrating peptides for improved drug delivery. Adv Drug Deliv Rev. 2017; 110–111:3–12.
   PubMed Web of Science ®Google Scholar
• Akhtar S, Benter IF. Nonviral delivery of synthetic siRNAs in vivo. J Clin Invest. 2007;117(12):3623–3632.
   PubMed Web of Science ®Google Scholar
• Strauss MH, Hall AS. The divergent cardiovascular effects of angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers in adult patients with type 2 diabetes mellitus. Can J Diabetes. 2018;42(2):124–129.
   PubMed Web of Science ®Google Scholar