Unravelling the Mechanistic Role of ACE2 and TMPRSS2 in Hypertension:
A Risk Factor for COVID-19

Nalini      Govender; Olive      Khaliq; Jagidesa      Moodley; Thajasvarie      Naicker
doi:10.2174/1573402118666220816090809
Abstract

Background: This review explores the mechanistic action of angiotensin-converting enzyme- 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) in the renin-angiotensinaldosterone system (RAAS) that predisposes hypertensive patients to the adverse outcome of severe COVID-19.
Methods and Results: Entry of SARS-CoV-2 into the host cell via ACE2 disrupts the RAAS system, creating an imbalance between ACE and ACE2, with an increased inflammatory response, leading to hypertension (HTN), pulmonary vasoconstriction and acute respiratory distress. SARSCoV- 2 may also predispose infected individuals with existing HTN to a greater risk of severe COVID-19 complications. In the duality of COVID-19 and HTN, the imbalance of ACE and ACE2 results in an elevation of AngII and a decrease in Ang (1-7), a hyperinflammatory response and endothelial dysfunction. Endothelial dysfunction is the main factor predisposing hypertensive patients to severe COVID-19 and vice-versa.
Conclusion: Despite the increase in ACE2 expression in hypertensive SARS-CoV-2 infected patients, ARBs/ACE inhibitors do not influence their severity and clinical outcomes, implicating continued usage. Future large-scale clinical trials are warranted to further elucidate the association between HTN and SARS-CoV-2 infection and the use of ARBs/ACEIs in SARS-CoV-2 hypertensive patients.
Keywords: ACE2, TMPRSS2, COVID-19, hypertension, RAAS, ARBs, ACEI.
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[1]
WHO. Coronavirus (COVID-19) Dashboard: World Health Organization 2022. Available from: https://covid19.who.int/

[2]
WHO Africa / Health topics / Coronavirus (COVID-19) World Health Organization 2022. Available from: https://www.afro. who.int/health-topics/coronavirus-covid-19

[3]
Cevik M, Grubaugh ND, Iwasaki A, Openshaw P. COVID-19 vaccines: Keeping pace with SARS-CoV-2 variants. Cell  2021; 184(20): 5077-81.
 [http://dx.doi.org/10.1016/j.cell.2021.09.010] [PMID: 34534444]

[4]
Tracking SARS-CoV-2 variantsWorld Health Organization 2022. Available from: https://www.who.int/en/activities/tracking-SARS-CoV-2-variants/

[5]
Viana R, Moyo S, Amoako DG, et al. Rapid epidemic expansion of the SARS-CoV-2 Omicron variant in southern Africa. Nature  2022; 603(7902): 679-86.
 [http://dx.doi.org/10.1038/s41586-022-04411-y] [PMID: 35042229]

[6]
Li X, Xu S, Yu M, et al. Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan. J Allergy Clin Immunol  2020; 146(1): 110-8.
 [http://dx.doi.org/10.1016/j.jaci.2020.04.006] [PMID: 32294485]

[7]
Simonnet A, Chetboun M, Poissy J, et al. High prevalence of obesity in severe acute respiratory syndrome coronavirus2 (SARS‐CoV‐2) requiring invasive mechanical ventilation. Obesity (Silver Spring)  2020; 28(7): 1195-9.
 [http://dx.doi.org/10.1002/oby.22831] [PMID: 32271993]

[8]
Chan JW, Ng CK, Chan YH, et al. Short term outcome and risk factors for adverse clinical outcomes in adults with severe acute respiratory syndrome (SARS). Thorax  2003; 58(8): 686-9.
 [http://dx.doi.org/10.1136/thorax.58.8.686] [PMID: 12885985]

[9]
Rezaei N, Montazeri F, Malekpour M-R, et al. COVID-19 in patients with diabetes: Factors associated with worse outcomes. J Diabetes Metab Disord  2021; 20: 1-10.
 [http://dx.doi.org/10.1007/s40200-021-00910-3] [PMID: 34729367]

[10]
Team E. The epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19)-China, 2020. China CDC Weekly  2020; 2(8): 113-22.
 [http://dx.doi.org/10.46234/ccdcw2020.032] [PMID: 34594836]

[11]
Shibata S, Arima H, Asayama K, et al. Hypertension and related diseases in the era of COVID-19: A report from the Japanese society of hypertension task force on COVID-19. Hypertens Res  2020; 43(10): 1028-46.
 [http://dx.doi.org/10.1038/s41440-020-0515-0] [PMID: 32737423]

[12]
Liu Y, Yang Y, Zhang C, et al. Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury. Sci China Life Sci  2020; 63(3): 364-74.
 [http://dx.doi.org/10.1007/s11427-020-1643-8] [PMID: 32048163]

[13]
Shen Y, Chang C, Zhang J, Jiang Y, Ni B, Wang Y. Prevalence and risk factors associated with hypertension and prehypertension in a working population at high altitude in China: A cross-sectional study. Environ Health Prev Med  2017; 22(1): 19.
 [http://dx.doi.org/10.1186/s12199-017-0634-7] [PMID: 29165123]

[14]
Hypertension Key factsWorld Health Organization 2021. Available from: https://www.who.int/news-room/fact-sheets/detail/hypertension

[15]
Sorato MM, Davari M, Kebriaeezadeh A, Sarrafzadegan N, Shibru T, Fatemi B. Reasons for poor blood pressure control in Eastern Sub-Saharan Africa: Looking into 4P’s (primary care, professional, patient, and public health policy) for improving blood pressure control: A scoping review. BMC Cardiovasc Disord  2021; 21(1): 123.
 [http://dx.doi.org/10.1186/s12872-021-01934-6] [PMID: 33663387]

[16]
Princewel F, Cumber SN, Kimbi JA, et al. Prevalence and risk factors associated with hypertension among adults in a rural setting: The case of Ombe, Cameroon. Pan Afr Med J  2019; 34: 147.
 [http://dx.doi.org/10.11604/pamj.2019.34.147.17518] [PMID: 32117515]

[17]
Asemu MM, Yalew AW, Kabeta ND, Mekonnen D. Prevalence and risk factors of hypertension among adults: A community based study in Addis Ababa, Ethiopia. PLoS One  2021; 16(4): e0248934.
 [http://dx.doi.org/10.1371/journal.pone.0248934] [PMID: 33793641]

[18]
Suleiman AK. Risk factors on hypertensive disorders among Jordanian pregnant women. Glob J Health Sci  2013; 6(2): 138-44.
 [http://dx.doi.org/10.5539/gjhs.v6n2p138] [PMID: 24576373]

[19]
Everett B, Zajacova A. Gender differences in hypertension and hypertension awareness among young adults. Biodemogr Soc Biol  2015; 61(1): 1-17.
 [http://dx.doi.org/10.1080/19485565.2014.929488] [PMID: 25879259]

[20]
Zhou B, Carrillo-Larco RM, Danaei G, et al. Worldwide trends in hypertension prevalence and progress in treatment and control from 1990 to 2019: A pooled analysis of 1201 population-representative studies with 104 million participants. Lancet  2021; 398(10304): 957-80.
 [http://dx.doi.org/10.1016/S0140-6736(21)01330-1] [PMID: 34450083]

[21]
Choi HM, Kim HC, Kang DR. Sex differences in hypertension prevalence and control: Analysis of the 2010-2014 Korea national health and nutrition examination survey. PLoS One  2017; 12(5): e0178334.
 [http://dx.doi.org/10.1371/journal.pone.0178334] [PMID: 28542557]

[22]
Santosa A, Zhang Y, Weinehall L, et al. Gender differences and determinants of prevalence, awareness, treatment and control of hypertension among adults in China and Sweden. BMC Public Health  2020; 20(1): 1763.
 [http://dx.doi.org/10.1186/s12889-020-09862-4] [PMID: 33228600]

[23]
Ghosh S, Mukhopadhyay S, Barik A. Sex differences in the risk profile of hypertension: A cross-sectional study. BMJ Open  2016; 6(7): e010085.
 [http://dx.doi.org/10.1136/bmjopen-2015-010085] [PMID: 27466234]

[24]
Ostchega Y, Fryar CD, Nwankwo T, Nguyen DT. Hypertension prevalence among adults aged 18 and over. United States 2017–2018 2020.

[25]
Global Health Observatory Data Repository 2015. Available from:
          http://apps.who.int/gho/data/node.main.A875STANDARD?lang=en

[26]
Hu G, Barengo NC, Tuomilehto J, Lakka TA, Nissinen A, Jousilahti P. Relationship of physical activity and body mass index to the risk of hypertension: A prospective study in Finland. Hypertension  2004; 43(1): 25-30.
 [http://dx.doi.org/10.1161/01.HYP.0000107400.72456.19] [PMID: 14656958]

[27]
Agaku IT, King BA, Dube SR. Current cigarette smoking among adults - United States, 2005-2012. MMWR Morb Mortal Wkly Rep  2014; 63(2): 29-34.
 [PMID: 24430098]

[28]
Flegal KM, Carroll MD, Kit BK, Ogden CL. Prevalence of obesity and trends in the distribution of body mass index among US adults, 1999-2010. JAMA  2012; 307(5): 491-7.
 [http://dx.doi.org/10.1001/jama.2012.39] [PMID: 22253363]

[29]
Bhatia K, Zimmerman MA, Sullivan JC. Sex differences in angiotensin-converting enzyme modulation of Ang (1-7) levels in normotensive WKY rats. Am J Hypertens  2013; 26(5): 591-8.
 [http://dx.doi.org/10.1093/ajh/hps088] [PMID: 23547034]

[30]
Maternal mortality ratio. World Health Organization 2019. internet  Available from: https://www.who.int/news-room/fact-sheets/detail/maternal-mortality

[31]
Magee LA, Brown MA, Hall DR, et al. The 2021 International Society for the study of hypertesion in pregnancy classification, diagnosis & management recommendations for international practice. Pregnancy Hypertens  2022; 27: 148-69.

[32]
Gathiram P, Moodley J. Pre-eclampsia: Its pathogenesis and pathophysiolgy. Cardiovasc J S Afr  2016; 27(2): 71-8.
 [http://dx.doi.org/10.5830/CVJA-2016-009] [PMID: 27213853]

[33]
Lu HQ, Hu R. Lasting effects of intrauterine exposure to preeclampsia on offspring and the underlying mechanism. AJP Rep  2019; 9(3): e275-91.
 [http://dx.doi.org/10.1055/s-0039-1695004] [PMID: 31511798]

[34]
Naidoo N, Moodley J, Naicker T. Maternal endothelial dysfunction in HIV-associated preeclampsia comorbid with COVID-19: A review. Hypertens Res  2021; 44(4): 386-98.
 [http://dx.doi.org/10.1038/s41440-020-00604-y] [PMID: 33469197]

[35]
Beevers G, Lip GY, O’Brien E. ABC of hypertension: The pathophysiology of hypertension. BMJ  2001; 322(7291): 912-6.
 [http://dx.doi.org/10.1136/bmj.322.7291.912] [PMID: 11302910]

[36]
Taddei S, Bruno RM, Masi S, Solini A. Epidemiology and pathophysiology of hypertension. In: Camm JA, Luscher TF, Maurer G, Serruys PW, Eds. ESC CardioMed Oxford.  United Kingdom: Oxford University Press 2018; pp. 2377-88.

[37]
Drenjančević-Perić I, Jelaković B, Lombard JH, Kunert MP, Kibel A, Gros M. High-salt diet and hypertension: Focus on the renin-angiotensin system. Kidney Blood Press Res  2011; 34(1): 1-11.
 [http://dx.doi.org/10.1159/000320387] [PMID: 21071956]

[38]
Reddy Gaddam R, Chambers S, Bhatia M. ACE and ACE2 in inflammation: A tale of two enzymes. Inflamm Allergy Drug Targets  2014; 13(4): 224-34.

[39]
Liu J, Zhou Y, Liu Y, et al. (Pro)renin- receptor regulates lung development via the Wnt/β-catenin signaling pathway. Am J Physiol Lung Cell Mol Physiol  2019; 317(2): L202-11.
 [http://dx.doi.org/10.1152/ajplung.00295.2018] [PMID: 31042081]

[40]
Ren L, Lu X, Danser AHJ. Revisiting the brain renin-angiotensin system-focus on novel therapies. Curr Hypertens Rep  2019; 21(4): 28.
 [http://dx.doi.org/10.1007/s11906-019-0937-8] [PMID: 30949864]

[41]
Fountain JH, Lappin SL. Physiology, renin- angiotensin system 2017.

[42]
de Souza AMA, West CA, de Abreu ARR, et al. Role of the renin- angiotensin system in blood pressure allostasis-induced by severe food restriction in female fischer rats. Sci Rep  2018; 8(1): 10327.
 [http://dx.doi.org/10.1038/s41598-018-28593-6] [PMID: 29985423]

[43]
Simões E, Silva AC. Teixeira MM. ACE inhibition, ACE2 and angiotensin-(1-7) axis in kidney and cardiac inflammation and fibrosis. Pharmacol Res  2016; 107: 154-62.
 [http://dx.doi.org/10.1016/j.phrs.2016.03.018] [PMID: 26995300]

[44]
McElwain CJ, Tuboly E, McCarthy FP, McCarthy CM. Mechanisms of endothelial dysfunction in pre-eclampsia and gestational diabetes mellitus: Windows into future cardiometabolic health? Front Endocrinol (Lausanne)  2020; 11: 655.
 [http://dx.doi.org/10.3389/fendo.2020.00655] [PMID: 33042016]

[45]
Tamanna S, Clifton VL, Rae K, van Helden DF, Lumbers ER, Pringle KG. Angiotensin Converting Enzyme 2 (ACE2) in pregnancy: Preeclampsia and small for gestational age. Front Physiol  2020; 11: 590787.
 [http://dx.doi.org/10.3389/fphys.2020.590787] [PMID: 33101066]

[46]
Merrill DC, Karoly M, Chen K, Ferrario CM, Brosnihan KB. Angiotensin-(1-7) in normal and preeclamptic pregnancy. Endocrine  2002; 18(3): 239-45.
 [http://dx.doi.org/10.1385/ENDO:18:3:239] [PMID: 12450315]

[47]
Xiao L, Sakagami H, Miwa N. ACE2: The key molecule for understanding the pathophysiology of severe and critical conditions of COVID-19: Demon or angel? Viruses  2020; 12(5): 491.
 [http://dx.doi.org/10.3390/v12050491] [PMID: 32354022]

[48]
D’Ardes D, Boccatonda A, Rossi I, et al. COVID-19 and RAS: Unravelling an unclear relationship. Int J Mol Sci  2020; 21(8): 3003.
 [http://dx.doi.org/10.3390/ijms21083003] [PMID: 32344526]

[49]
Bian J, Li Z. Angiotensin-converting enzyme 2 (ACE2): SARS-CoV-2 receptor and RAS modulator. Acta Pharm Sin B  2021; 11(1): 1-12.
 [http://dx.doi.org/10.1016/j.apsb.2020.10.006] [PMID: 33072500]

[50]
Shang J, Wan Y, Luo C, et al. Cell entry mechanisms of SARS-CoV-2. Proc Natl Acad Sci USA  2020; 117(21): 11727-34.
 [http://dx.doi.org/10.1073/pnas.2003138117] [PMID: 32376634]

[51]
Heald-Sargent T, Gallagher T. Ready, set, fuse! The coronavirus spike protein and acquisition of fusion competence. Viruses  2012; 4(4): 557-80.
 [http://dx.doi.org/10.3390/v4040557] [PMID: 22590686]

[52]
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: 271-80.

[53]
Verdecchia P, Cavallini C, Spanevello A, Angeli F. The pivotal link between ACE2 deficiency and SARS-CoV-2 infection. Eur J Intern Med  2020; 76: 14-20.
 [http://dx.doi.org/10.1016/j.ejim.2020.04.037] [PMID: 32336612]

[54]
Albini A, Di Guardo G, Noonan DM, Lombardo M. The SARS-CoV-2 receptor, ACE-2, is expressed on many different cell types: Implications for ACE-inhibitor- and angiotensin II receptor blocker-based cardiovascular therapies. Intern Emerg Med  2020; 15(5): 759-66.
 [http://dx.doi.org/10.1007/s11739-020-02364-6] [PMID: 32430651]

[55]
Tikellis C, Thomas M. Angiotensin-Converting Enzyme 2 (ACE2) is a key modulator of the renin- angiotensin system in health and disease. Int J Pept  2012; 2012: 256294.

[56]
Hoffmann M, Kleine-Weber H, Pöhlmann S. A multibasic cleavage site in the spike protein of SARS-CoV-2 is essential for infection of human lung cells. Mol Cell  2020; 78: 779-84.

[57]
Heurich A, Hofmann-Winkler H, Gierer S, Liepold T, Jahn O, Pöhlmann S. TMPRSS2 and ADAM17 cleave ACE2 differentially and only proteolysis by TMPRSS2 augments entry driven by the severe acute respiratory syndrome coronavirus spike protein. J Virol  2014; 88(2): 1293-307.
 [http://dx.doi.org/10.1128/JVI.02202-13] [PMID: 24227843]

[58]
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): 565-71.
 [http://dx.doi.org/10.1016/j.cardfail.2009.01.014] [PMID: 19700132]

[59]
Lambert DW, Yarski M, Warner FJ, et al. Tumor necrosis factor-α 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): 30113-9.
 [http://dx.doi.org/10.1074/jbc.M505111200] [PMID: 15983030]

[60]
Xia S, Liu M, Wang C, et al. Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion. Cell Res  2020; 30(4): 343-55.
 [http://dx.doi.org/10.1038/s41422-020-0305-x] [PMID: 32231345]

[61]
Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science  2020; 367(6485): 1444-8.
 [http://dx.doi.org/10.1126/science.abb2762] [PMID: 32132184]

[62]
Yang X, Yu Y, Xu J, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: A single-centered, retrospective, observational study. Lancet Respir Med  2020; 8(5): 475-81.
 [http://dx.doi.org/10.1016/S2213-2600(20)30079-5] [PMID: 32105632]

[63]
Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus–infected pneumonia in Wuhan, China. JAMA  2020; 323(11): 1061-9.
 [http://dx.doi.org/10.1001/jama.2020.1585] [PMID: 32031570]

[64]
Bhandari S, Bhargava A, Sharma S, Keshwani P, Sharma R, Banerjee S. Clinical profile of Covid-19 infected patients admitted in a tertiary care hospital in North India. J Assoc Physicians India  2020; 68(5): 13-7.
 [PMID: 32610859]

[65]
Guan WJ, Ni ZY, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med  2020; 382(18): 1708-20.
 [http://dx.doi.org/10.1056/NEJMoa2002032] [PMID: 32109013]

[66]
Zhang JJ, Dong X, Cao YY, et al. Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China. Allergy  2020; 75(7): 1730-41.
 [http://dx.doi.org/10.1111/all.14238] [PMID: 32077115]

[67]
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): 1054-62.
 [http://dx.doi.org/10.1016/S0140-6736(20)30566-3] [PMID: 32171076]

[68]
Hsueh WA, Wyne K. Renin-angiotensin-aldosterone system in diabetes and hypertension. J Clin Hypertens (Greenwich)  2011; 13(4): 224-37.
 [http://dx.doi.org/10.1111/j.1751-7176.2011.00449.x] [PMID: 21466617]

[69]
Daher J. Endothelial dysfunction and COVID-19. (Review). Biomed Rep  2021; 15(6): 102.
 [http://dx.doi.org/10.3892/br.2021.1478] [PMID: 34667599]

[70]
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): 1818-20.
 [http://dx.doi.org/10.1093/eurheartj/ehaa414] [PMID: 32388547]

[71]
Li J, Wang X, Chen J, Zhang H, Deng A. 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): 825-30.
 [http://dx.doi.org/10.1001/jamacardio.2020.1624] [PMID: 32324209]

[72]
Gill D, Arvanitis M, Carter P, et al. ACE inhibition and cardiometabolic risk factors, lung ACE2 and TMPRSS2 gene expression, and plasma ACE2 levels: A Mendelian randomization study. R Soc Open Sci  2020; 7(11): 200958.
 [http://dx.doi.org/10.1098/rsos.200958] [PMID: 33391794]

[73]
Saha S, Chakrabarti S, Singh PK, et al. Physiological relevance of angiotensin converting enzyme 2 as a metabolic linker and therapeutic implication of mesenchymal stem cells in COVID-19 and hypertension. Stem Cell Rev Rep  2021; 17(1): 132-43.
 [http://dx.doi.org/10.1007/s12015-020-10012-x] [PMID: 32748331]

[74]
Klhůfek J. The role of angiotensin-converting enzyme 2 in the pathogenesis of COVID-19: The villain or the hero? Acta Clin Belg  2022; 77(1): 211-8.
 [PMID: 32597377]

[75]
Ramphal S, Govender N, Singh S, Khaliq OP, Naicker T. Histopathological features in advanced abdominal pregnancies co-infected with SARS-CoV-2 and HIV-1 infections: A case evaluation. Eur J Obstet Gynecol Reprod Biol X  2022; 15: 100153.
 [http://dx.doi.org/10.1016/j.eurox.2022.100153] [PMID: 35600136]

[76]
Guan WJ, Liang WH, Zhao Y, et al. Comorbidity and its impact on 1590 patients with COVID-19 in China: A nationwide analysis. Eur Respir J  2020; 55(5): 55.
 [http://dx.doi.org/10.1183/13993003.00547-2020] [PMID: 32217650]

[77]
Dalan R, Bornstein SR, El-Armouche A, et al. The ACE-2 in COVID-19: Foe or friend? Horm Metab Res  2020; 52(5): 257-63.
 [http://dx.doi.org/10.1055/a-1155-0501] [PMID: 32340044]

[78]
Zhao Y, Zhao Z, Wang Y, Zhou Y, Ma Y, Zuo W. Single-cell RNA expression profiling of ACE2, the receptor of SARS-CoV-2. Am J Respir Crit Care Med  2020; 202(5): 756-9.
 [http://dx.doi.org/10.1164/rccm.202001-0179LE] [PMID: 32663409]

[79]
Swärd P, Edsfeldt A, Reepalu A, Jehpsson L, Rosengren BE, Karlsson MK. Age and sex differences in soluble ACE2 may give insights for COVID-19. Crit Care  2020; 24(1): 221.
 [http://dx.doi.org/10.1186/s13054-020-02942-2] [PMID: 32410690]

[80]
Baughn LB, Sharma N, Elhaik E, Sekulic A, Bryce AH, Fonseca R. Targeting TMPRSS2 in SARS-CoV-2 infection. Mayo Clin Proc  2020; 95(9): 1989-99.

[81]
Co COC, Yu JRT, Laxamana LC, David-Ona DIA. Intravenous thrombolysis for stroke in a COVID-19 positive Filipino patient, a case report. J Clin Neurosci  2020; 77: 234-6.
 [http://dx.doi.org/10.1016/j.jocn.2020.05.006] [PMID: 32414622]

[82]
Avula A, Nalleballe K, Narula N, et al. COVID-19 presenting as stroke. Brain Behav Immun  2020; 87: 115-9.
 [http://dx.doi.org/10.1016/j.bbi.2020.04.077] [PMID: 32360439]

[83]
Vieira C, Nery L, Martins L, et al. Downregulation of membrane-bound Angiotensin Converting Enzyme 2 (ACE2) receptor has a pivotal role in COVID-19 immunopathology. Curr Drug Targets  2021; 22(3): 254-81.
 [http://dx.doi.org/10.2174/1389450121666201020154033] [PMID: 33081670]

[84]
Guirao JJ, Cabrera CM, Jiménez N, Rincón L, Urra JM. High serum IL-6 values increase the risk of mortality and the severity of pneumonia in patients diagnosed with COVID-19. Mol Immunol  2020; 128: 64-8.
 [http://dx.doi.org/10.1016/j.molimm.2020.10.006] [PMID: 33075636]

[85]
Zores F, Rebeaud ME. COVID and the renin-angiotensin system: Are hypertension or its treatments deleterious? Front Cardiovasc Med  2020; 7: 71.
 [http://dx.doi.org/10.3389/fcvm.2020.00071] [PMID: 32391384]

[86]
Mackey K, King VJ, Gurley S, et al. Risks and impact of angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers on SARS-CoV-2 infection in adults: A living systematic review. Ann Intern Med  2020; 173(3): 195-203.
 [http://dx.doi.org/10.7326/M20-1515] [PMID: 32422062]

[87]
Cordeanu E-M, Jambert L, Severac F, et al. Outcomes of COVID-19 hospitalized patients previously treated with renin-angiotensin system inhibitors. J Clin Med  2020; 9(11): 3472.
 [http://dx.doi.org/10.3390/jcm9113472] [PMID: 33126565]

[88]
Soler MJ, Ribera A, Marsal JR, et al. Association of renin-angiotensin system blockers with COVID-19 diagnosis and prognosis in patients with hypertension: A population-based study. Clin Kidney J  2021; 15(1): 79-94.
 [http://dx.doi.org/10.1093/ckj/sfab161] [PMID: 35035939]

[89]
Soler MJ, Ye M, Wysocki J, William J, Lloveras J, Batlle D. 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): F398-405.
 [http://dx.doi.org/10.1152/ajprenal.90488.2008] [PMID: 19004932]

[90]
Carey RM. AT2 receptors: Potential therapeutic targets for hypertension. Am J Hypertens  2017; 30(4): 339-47.
 [PMID: 27664954]

[91]
South AM, Brady TM, Flynn JT. ACE2 (angiotensin-converting enzyme 2), COVID-19, and ACE inhibitor and Ang II (angiotensin II) receptor blocker use during the pandemic: The pediatric perspective. Hypertension  2020; 76(1): 16-22.
 [http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.15291] [PMID: 32367746]

[92]
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  2005; 111(20): 2605-10.
 [http://dx.doi.org/10.1161/CIRCULATIONAHA.104.510461] [PMID: 15897343]

[93]
Chen J, Liu Y, Qin J, et al. Hypertension as an independent risk factor for severity and mortality in patients with COVID-19: A retrospective study. Postgrad Med J  2021; postgradmedj-2021-140674
 [http://dx.doi.org/10.1136/postgradmedj-2021-140674] [PMID: 34611036]

[94]
Kai H, Kai M. Interactions of coronaviruses with ACE2, angiotensin II, and RAS inhibitors-lessons from available evidence and insights into COVID-19. Hypertens Res  2020; 43(7): 648-54.
 [http://dx.doi.org/10.1038/s41440-020-0455-8] [PMID: 32341442]

[95]
Clerkin KJ, Fried JA, Raikhelkar J, et al. COVID-19 and cardiovascular disease. Circulation  2020; 141(20): 1648-55.
 [http://dx.doi.org/10.1161/CIRCULATIONAHA.120.046941] [PMID: 32200663]
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DOI https://dx.doi.org/10.2174/1573402118666220816090809	Print ISSN 1573-4021
Publisher Name Bentham Science Publisher	Online ISSN 1875-6506
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Unravelling the Mechanistic Role of ACE2 and TMPRSS2 in Hypertension: A Risk Factor for COVID-19

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