Main Article Content
Abstract
The Renin-angiotensin system (RAS) plays an important role in the SARS-CoV-2 infection through Angiotensin-converting enzyme 2 (ACE2). Human recombinant soluble ACE2 (hrsACE2) has been shown to act as a competitive interceptor for SARS-CoV-2 by preventing the binding of viral particles to the ACE2. In addition, Rho-kinase inhibitors have been proven to suppress SARS-CoV-2 infection through inhibition of the Rho-associated protein kinase (ROCK) pathway. The combined effect of hrsACE2 and Rho-kinase inhibitor increases the activity and levels of ACE2 in protection through the Ang1-7 MasR, Ang1-9, and other mechanisms of protection. This literature review is done by searching journals with “COVID-19”, “ACE2”, “hrsACE2”, “Rho- kinase inhibitor”, and “ROCK pathway” as well as Boolean logic “AND” and “OR”. Relevant journals are used as references to compile systematic writing. Based on research results, hrsACE2 and Rho-kinase inhibitors have been clinically proven to protect tissue through the elevated level of ACE2 by the mechanism of Rho-kinase inhibitor, which increased Ang1-7 MasR concentration that gives vasodilatation, anti-proliferative, anti-inflammation, and anti-fibrotic effect. Rho-kinase inhibitors significantly reduce the number of infected cells by SARS-CoV-2 in COVID-19 patients. The potential of the combination therapy of Rho-kinase inhibitor and hrsACE2 therapy can be an efficient therapeutic solution for COVID-19 patients so that further research can be carried out in the future.
Keywords
Article Details
This work is licensed under a Creative Commons Attribution 4.0 International License.
References
- 1. Yi Y, Lagniton PNP, Ye S, Li E, Xu R-H. COVID-19: what has been learned and to be learned about the novel coronavirus disease. Int J Biol Sci [Internet]. 2020 Mar 15;16(10):1753–66. Available from: https://pubmed. ncbi.nlm.nih.gov/32226295
- 2. World Health Organization. WHO Coronavirus (COVID-19) Dashboard. 2021; Available from: https://covid19.who.int
- 3. Kementrian Kesehatan Republik Indonesia. Situasi Terkini Perkembangan Coronavirus Disease (COVID-19) 08 April 2021. 2021; Available from: https://infeksiemerging.kemkes.go.id/situasi-infeksi-emerging/situasi-terkini-perkembangan-coronavirus-disease-covid-19-08-april-2021#
- 4. Cugno M, Gualtierotti R, Casazza G, Tafuri F, Ghigliazza G, Torri A, et al. Mortality in Patients with COVID-19 on Renin Angiotensin System Inhibitor Long-Term Treatment: An Observational Study Showing that Things Are Not Always as They Seem. Adv Ther [Internet]. 2021; Available from: https://doi.org/10.1007/s12325-021-01704-y
- 5. Instiaty, Sri Darmayani IGAAP, Marzuki JE, Angelia F, William, Siane A, et al. Antiviral treatment of covid-19: A clinical pharmacology narrative review. Med J Indones [Internet]. 2020;29(3):332–45. Available from: http://dx.doi.org/10.13181/mji.rev.204652
- 6. Agrawal U, Raju R, Udwadia ZF. Favipiravir: A new and emerging antiviral option in COVID-19. Med J Armed Forces India [Internet]. 2020;76(4):370–6. Available from: https://doi.org/10.1016/j.mjafi.2020.08.004
- 7. Bourgonje AR, Abdulle AE, Timens W, Hillebrands J-L, Navis GJ, Gordijn SJ, et al. Angiotensin-converting enzyme 2 (ACE2), SARS-CoV-2 and the pathophysiology of coronavirus disease 2019 (COVID-19). J Pathol [Internet]. 2020/06/10. 2020 Jul;251(3):228–48. Available from: https://pubmed.ncbi.nlm.nih.gov/32418199
- 8. Zhang H, Penninger JM, Li Y, Zhong N, Slutsky AS. Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Med [Internet]. 2020;46(4):586–90. Available from: https://doi.org/10.1007/s00134-020-05985-9
- 9. Monteil V, Kwon H, Prado P, Hagelkrüys A, Wimmer RA, Stahl M, et al. Inhibition of SARS-CoV-2 Infections in Engineered Human Tissues Using Clinical-Grade Soluble Human ACE2. Cell. 2020 May;181(4):905-913.e7.
- 10. Urciuoli E, Peruzzi B. Inhibiting Extracellular Vesicle Trafficking as Antiviral Approach to Corona Virus Disease 2019 Infection. Front Pharmacol. 2020;11(September):1–6.
- 11. Sedgwick AE, Clancy JW, Olivia Balmert M, D’Souza-Schorey C. Extracellular microvesicles and invadopodia mediate non-overlapping modes of tumor cell invasion. Sci Rep [Internet]. 2015;5(1):14748. Available from: https://doi.org/10.1038/srep14748
- 12. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China. JAMA [Internet]. 2020 Mar 17;323(11):1061–9. Available from: https://doi.org/10.1001/jama.2020.1585
- 13. Chan JF-W, Yuan S, Kok K-H, To KK-W, Chu H, Yang J, et al. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet [Internet]. 2020 Feb 15;395(10223):514–23. Available from: https://doi.org/10.1016/S0140-6736(20)30154-9
- 14. Ni W, Yang X, Yang D, Bao J, Li R, Xiao Y, et al. Role of angiotensin-converting enzyme 2 (ACE2) in COVID-19. Crit Care [Internet]. 2020;24(1):422. Available from: https://doi.org/10.1186/s13054-020-03120-0
- 15. Zou X, Chen K, Zou J, Han P, Hao J, Han Z. Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection. Front Med. 2020 Apr;14(2):185–92.
- 16. Lauer SA, Grantz KH, Bi Q, Jones FK, Zheng Q, Meredith HR, et al. The Incubation Period of Coronavirus Disease 2019 (COVID-19) From Publicly Reported Confirmed Cases: Estimation and Application. Ann Intern Med [Internet]. 2020/03/10. 2020 May 5;172(9):577–82. Available from: https://pubmed.ncbi.nlm.nih.gov/32150748
- 17. Giannessi F, Aiello A, Franchi F, Percario ZA, Affabris E. The Role of Extracellular Vesicles as Allies of HIV, HCV and SARS Viruses. Viruses [Internet]. 2020 May 22;12(5):571. Available from: https://pubmed.ncbi.nlm.nih.gov/32456011
- 18. Doyle LM, Wang MZ. Overview of Extracellular Vesicles, Their Origin, Composition, Purpose, and Methods for Exosome Isolation and Analysis. Cells [Internet]. 2019 Jul 15;8(7):727. Available from: https://pubmed.ncbi.nlm.nih.gov/31311206
- 19. Patil AA, Rhee WJ. Exosomes: Biogenesis, Composition, Functions, and Their Role in Pre-metastatic Niche Formation. Biotechnol Bioprocess Eng [Internet]. 2019;24(5):689–701. Available from: https://doi.org/10.1007/s12257-019-0170-y
- 20. Nolte-’t Hoen E, Cremer T, Gallo RC, Margolis LB. Extracellular vesicles and viruses: Are they close relatives? Proc Natl Acad Sci U S A [Internet]. 2016/07/18. 2016 Aug 16;113(33):9155–61. Available from: https://pubmed.ncbi.nlm.nih.gov/27432966
- 21. Stancioiu F, Papadakis Z. G, Kteniadakis S, Izotov Nikovaevich B, Coleman D. M, Spandidos A. D, et al. A dissection of SARS‑CoV2 with clinical implications (Review). Int J Mol Med [Internet]. 2020;46(2):489–508. Available from: https://doi.org/10.3892/ijmm.2020.4636
- 22. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020 Apr;181(2):271-280.e8.
- 23. Li Y, Zhou W, Yang L, You R. Physiological and pathological regulation of ACE2, the SARS-CoV-2 receptor. Pharmacol Res. 2020 Jul;157:104833.
- 24. Bernstein KE, Khan Z, Giani JF, Cao D-Y, Bernstein EA, Shen XZ. Angiotensin-converting enzyme in innate and adaptive immunity. Nat Rev Nephrol. 2018 May;14(5):325–36.
- 25. Yamamoto S, Yancey PG, Zuo Y, Ma L-J, Kaseda R, Fogo AB, et al. Macrophage polarization by angiotensin II-type 1 receptor aggravates renal injury-acceleration of atherosclerosis. Arterioscler Thromb Vasc Biol. 2011 Dec;31(12):2856–64.
- 26. Li C, Liu P-P, Tang D-D, Song R, Zhang Y-Q, Lei S, et al. Targeting the RhoA-ROCK pathway to regulate T-cell homeostasis in hypoxia-induced pulmonary arterial hypertension. Pulm Pharmacol & Ther [Internet]. 2018;50:111–22. Available from: http://europepmc.org/abstract/MED/29673911
- 27. Ocaranza MP, Rivera P, Novoa U, Pinto M, González L, Chiong M, et al. Rho kinase inhibition activates the homologous angiotensin-converting enzyme-angiotensin-(1-9) axis in experimental hypertension. J Hypertens. 2011 Apr;29(4):706–15.
- 28. Khodarahmi R, Sayad B, Sobhani M. The ACE2 as a “rescue protein” or “suspect enzyme” in COVID-19: possible application of the “engineered inactive hrsACE2” as a safer therapeutic agent in the treatment of SARS-CoV-2 infection. J Iran Chem Soc [Internet]. 2021;18(3):495–502. Available from: https://doi.org/10.1007/s13738-020-02049-z
- 29. Zoufaly A, Poglitsch M, Aberle JH, Hoepler W, Seitz T, Traugott M, et al. Human recombinant soluble ACE2 in severe COVID-19. Lancet Respir Med. 2020 Nov;8(11):1154–8.
- 30. Amen Y, Zhu Q, Tran H-B, Afifi MS, Halim AF, Ashour A, et al. Rho-kinase inhibitors from adlay seeds. Nat Prod Res. 2018 Aug;32(16):1955–9.
- 31. Abedi F, Rezaee R, Karimi G. Plausibility of therapeutic effects of Rho kinase inhibitors against Severe Acute Respiratory Syndrome Coronavirus 2 (COVID-19). Vol. 156, Pharmacological research. 2020. p. 104808.
- 32. Haschke M, Schuster M, Poglitsch M, Loibner H, Salzberg M, Bruggisser M, et al. Pharmacokinetics and pharmacodynamics of recombinant human angiotensin-converting enzyme 2 in healthy human subjects. Clin Pharmacokinet. 2013;52(9):783–92.
- 33. Abd El-Aziz TM, Al-Sabi A, Stockand JD. Human recombinant soluble ACE2 (hrsACE2) shows promise for treating severe COVID19. Signal Transduct Target Ther [Internet]. 2020;5(1):3–4. Available from: http://dx.doi.org/10.1038/s41392-020-00374-6
- 34. Gupta V, Gupta N, Shaik IH, Mehvar R, McMurtry IF, Oka M, et al. Liposomal fasudil, a rho-kinase inhibitor, for prolonged pulmonary preferential vasodilation in pulmonary arterial hypertension. J Control Release [Internet]. 2013;167(2):189–99. Available from: http://dx.doi.org/10.1016/j.jconrel.2013.01.011
- 35. Indijah, Woro S, Fajri, Purnama, Saputri, Leo N. Modul Bahan Ajar Cetak Farmasi : Farmakologi [Internet]. 1st ed. Pusdik SDM Kesehatan. Jakarta: Kementrian Kesehatan RI; 2016. Available from: http://marefateadyan.nashriyat.ir/node/150
- 36. Zamai L. The Yin and Yang of ACE/ACE2 Pathways: The Rationale for the Use of Renin-Angiotensin System Inhibitors in COVID-19 Patients. Cells. 2020 Jul;9(7):1704.
- 37. Rudokas M, Najlah M, Alhnan MA, Elhissi A. Liposome Delivery Systems for Inhalation: A Critical Review Highlighting Formulation Issues and Anticancer Applications. Med Princ Pract. 2016;25(suppl 2)(Suppl. 2):60–72.
- 38. Sercombe L, Veerati T, Moheimani F, Wu SY, Sood AK, Hua S. Advances and Challenges of Liposome Assisted Drug Delivery. Front Pharmacol. 2015;6:286.
- 39. Batlle D, Wysocki J, Satchell K. Soluble angiotensin-converting enzyme 2: a potential approach for coronavirus infection therapy? Vol. 134, Clinical science (London, England : 1979). England; 2020. p. 543–5.
- 40. Guan W, Ni Z, Hu Y, Liang W, Ou C, He J, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020 Feb;382(18):1708–20.
- 41. Walls AC, Park Y-J, Tortorici MA, Wall A, McGuire AT, Veesler D. Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein. Cell. 2020;181(2):281-292.e6.
- 42. Xu X, Shi L, Ma X, Su H, Ma G, Wu X, et al. RhoA-Rho associated kinase signaling leads to renin-angiotensin system imbalance and angiotensin converting enzyme 2 has a protective role in acute pulmonary embolism. Thromb Res. 2019 Apr;176:85–94.
- 43. Li B, Antonyak MA, Zhang J, Cerione RA. RhoA triggers a specific signaling pathway that generates transforming microvesicles in cancer cells. Oncogene. 2012 Nov;31(45):4740–9.
- 44. Calò LA, Facco M, Davis PA, Pagnin E, Maso LD, Puato M, et al. Endothelial progenitor cells relationships with clinical and biochemical factors in a human model of blunted angiotensin II signaling. Hypertens Res. 2011;34(9):1017–22.
- 45. Calò LA, Davis PA, Rossi GP. Understanding the mechanisms of angiotensin II signaling involved in hypertension and its long-term sequelae: insights from Bartter’s and Gitelman’s syndromes, human models of endogenous angiotensin II signaling antagonism. J Hypertens. 2014;32(11):2109–19; discussion 2119.
- 46. Kuriakose J, Montezano AC, Touyz RM. ACE2/Ang-(1-7)/Mas1 axis and the vascular system: vasoprotection to COVID-19-associated vascular disease. Clin Sci (Lond). 2021 Jan;135(2):387–407.
- 47. Santos RAS, Sampaio WO, Alzamora AC, Motta-Santos D, Alenina N, Bader M, et al. The ACE2/Angiotensin-(1–7)/MAS Axis of the Renin-Angiotensin System: Focus on Angiotensin-(1–7). Physiol Rev. 2017 Dec;98(1):505–53.
- 48. Augusto SR. Angiotensin-(1–7). Hypertension. 2014 Jun;63(6):1138–47.
- 49. Mendoza-Torres E, Oyarzún A, Mondaca-Ruff D, Azocar A, Castro PF, Jalil JE, et al. ACE2 and vasoactive peptides: novel players in cardiovascular/renal remodeling and hypertension. Ther Adv Cardiovasc Dis. 2015 Aug;9(4):217–37.
- 50. Shete A. Urgent need for evaluating agonists of angiotensin-(1-7)/Mas receptor axis for treating patients with COVID-19. Int J Infect Dis IJID Off Publ Int Soc Infect Dis. 2020 Jul;96:348–51.
- 51. Cox MJ, Lucien F, Sakemura R, Boysen JC, Kim Y, Horvei P, et al. Leukemic extracellular vesicles induce chimeric antigen receptor T cell dysfunction in chronic lymphocytic leukemia. Mol Ther. 2021;29(4):1529–40.
- 52. Latham SL, Chaponnier C, Dugina V, Couraud P-O, Grau GER, Combes V. Cooperation between β- and γ-cytoplasmic actins in the mechanical regulation of endothelial microparticle formation. FASEB J Off Publ Fed Am Soc Exp Biol. 2013 Feb;27(2):672–83.
- 53. Zhang S, Liu Y, Wang X, Yang L, Li H, Wang Y, et al. SARS-CoV-2 binds platelet ACE2 to enhance thrombosis in COVID-19. J Hematol Oncol. 2020 Sep;13(1):120.
- 54. Khan A, Benthin C, Zeno B, Albertson TE, Boyd J, Christie JD, et al. A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome. Crit Care. 2017 Sep;21(1):234.
- 55. Ding R, Zhao D, Li X, Liu B, Ma X. Rho-kinase inhibitor treatment prevents pulmonary inflammation and coagulation in lipopolysaccharide-induced lung injury. Thromb Res. 2017 Feb;150:59–64.
- 56. Cantoni S, Cavalli S, Pastore F, Accetta A, Pala D, Vaccaro F, et al. Pharmacological characterization of a highly selective Rho kinase (ROCK) inhibitor and its therapeutic effects in experimental pulmonary hypertension. Eur J Pharmacol. 2019 May;850:126–34.