Losartan Has a Comparable Effect to Human Recombinant ACE2 in Reducing Interleukin-6 (IL-6) Levels on Human Adipocytes Exposed to SARS-CoV-2 Spike Protein

Hanestya Oky Hermawan, Meity Ardiana, I Gde Rurus Suryawan, Primasitha Maharany Harsoyo, Muhammad Rafli


BACKGROUND: High angiotensin-converting enzyme 2 (ACE2) expression in adipocyte cells facilitates the initiation of SARS-CoV-2 infection and triggers a cytokine storm. This finding suggests that obesity is an independent risk factor for the severity of the symptoms caused by COVID-19. The use of cardiovascular medications that focus on ACE2, such as angiotensin II receptor blockers, remains controversial, and their effects on inflammatory cytokine production and ACE2 expression in cells, especially adipocytes, remain inconsistent.

METHODS: The human adipocytes were isolated from obese donor subcutaneous adipose tissue and infected with the subunit S1 spike protein from SARS-Cov-2. The adipocytes were later treated with either hrsACE2 or losartan. The levels of ACE2 and inflammatory cytokines interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α were measured using enzyme linked immunosorbent assay (ELISA). ACE2 and S1 spike protein binding assays were also performed.

RESULTS: ACE2, IL-6, and TNF-α levels were significantly increased in human adipocyte cells infected with SARS-Cov-2 but not IL-1β. There was a statistically significant positive correlation between ACE2 and IL-6 (r=0.878, p<0.001). Administration of losartan and hrsACE2 was shown to reduce ACE2 levels and its binding to the SARS-CoV-2 S1 spike protein, and IL-6 levels were statistically significant, but had no significant effect on IL-1β or TNF-α levels.

CONCLUSION: This study shows that the administration of losartan in COVID-19 may not be harmful, but instead has a protective effect similar to that of hrsACE2 in preventing a cytokine storm, especially IL-6.

KEYWORDS: obesity, SARS-CoV-2, losartan, IL-6, ACE2

Full Text:



Tandirogang N, Fitriany E, Mardania N, Jannah M, Dilan BFN, Ratri SR, et al. Neutralizing antibody response by inactivated SARS-CoV-2 vaccine on healthcare workers. Mol Cell Biomed Sci. 2023; 7(1): 18-27, CrossRef.

Simonnet A, Chetboun M, Poissy J, Raverdy V, Noulette J, Duhamel A, et al. High prevalence of obesity in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) requiring invasive mechanical ventilation. Obesity. 2020; 28(7): 1195-9, CrossRef.

Petrilli CM, Jones SA, Yang J, Rajagopalan H, O’Donnell L, Chernyak Y, et al. Factors associated with hospital admission and critical illness among 5279 people with coronavirus disease 2019 in New York City: Prospective cohort study. Brit Med J. 2020; 369(m1966): 1–15, CrossRef.

Lighter J, Phillips M, Hochman S, Sterling S, Johnson D, Francois F, et al. Obesity in patients younger than 60 years is a risk factor for COVID-19 hospital admission. Clin Infect Dis. 2020; 71(15): 896-7, CrossRef.

Meiliana A, Dewi NM, Wijaya A. Current progress in adipose tissue biology: Implications in obesity and its comorbidities. Indones Biomed J. 2020; 12(2): 85-101, CrossRef.

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. 2020; 24(1): 422, CrossRef.

Li W, Moore MJ, Vasllieva N, Sui J, Wong SK, Berne MA, et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature. 2003; 426(6965): 450-4, CrossRef.

Ryan PM, Caplice NM. Is adipose tissue a reservoir for viral spread, immune activation, and cytokine amplification in coronavirus disease 2019? Obesity. 2020; 28(7): 1191-4, CrossRef.

Fontana L, Eagon JC, Trujillo ME, Scherer PE, Klein S. Visceral fat adipokine secretion is associated with systemic inflammation in obese humans. Diabetes. 2007; 56(4): 1010-3, CrossRef.

Mohamed-Ali V, Goodrick S, Rawesh A, Katz DR, Miles JM, Yudkin JS, et al. Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-α, in vivo. J Clin Endocrinol Metab. 1997; 82(12): 4196-200, CrossRef.

Chen X, Zhao B, Qu Y, Chen Y, Xiong J, Feng Y, et al. Detectable serum SARS-CoV-2 viral load (RNAaemia) is closely correlated with drastically elevated interleukin 6 (IL-6) level in critically ill COVID-19 patients. Clin Infect Dis. 2020; 71(8): 1937-42, CrossRef.

Ulhaq ZS, Soraya GV. Interleukin-6 as a potential biomarker of COVID-19 progression. Med Mal Infect. 2020; 50(4): 382-3, CrossRef.

Al-Benna S. Association of high level gene expression of ACE2 in adipose tissue with mortality of COVID-19 infection in obese patients. Obes Med. 2020; 19: 100283, CrossRef.

Jia X, Yin C, Lu S, Chen Y, Liu Q, Bai J, et al. Two things about COVID-19 might need attention. Preprints. 2020; n.v.: 2020020315, CrossRef.

Tikellis C, Thomas MC. Angiotensin-converting enzyme 2 (ACE2) is a key modulator of the renin angiotensin system in health and disease. Int J Pept. 2012; 2012: 256294, CrossRef.

Kai H, Kai M, Niiyama H, Okina N, Sasaki M, Maeda T, et al. Overexpression of angiotensin-converting enzyme 2 by renin-angiotensin system inhibitors. Truth or myth? A systematic review of animal studies. Hypertension Res. 2021; 44(8): 955-68, CrossRef.

Gheblawi M, Wang K, Viveiros A, Nguyen Q, Zhong JC, Turner AJ, et al. 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; 126(10): 1456-74, CrossRef.

Carswell KA, Lee MJ, Fried SK. Culture of isolated human adipocytes and isolated adipose tissue. Methods Mol Biol. 2012; 806: 203-14, CrossRef.

Buzhdygan TP, DeOre BJ, Baldwin-Leclair A, Bullock TA, McGary HM, Khan JA, et al. The SARS-CoV-2 spike protein alters barrier function in 2D static and 3D microfluidic in-vitro models of the human blood–brain barrier. Neurobiol Dis. 2020; 146: 105131, CrossRef.

Ferrario CM, Jessup J, Chappell MC, Averill DB, Brosnihan KB, Tallant EA, 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, CrossRef.

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; 181(4): 905-13.e7, CrossRef.

Zhang H, Baker A. Recombinant human ACE2: Acing out angiotensin II in ARDS therapy. Crit Care. 2017; 21(1): 305, CrossRef.

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; 21(1): 234, CrossRef.

Pang X, Cui Y, Zhu Y. Recombinant human ACE2: Potential therapeutics of SARS-CoV-2 infection and its complication. Acta Pharmacol Sin. 2020; 41(9): 1255-7, CrossRef.

Maurya R, Sebastian P, Namdeo M, Devender M, Gertler A. COVID-19 Severity in obesity: Leptin and inflammatory cytokine interplay in the link between high morbidity and mortality. Front Immunol. 2021; 12: 649359, CrossRef.

Fain JN, Madan AK, Hiler ML, Cheema P, Bahouth SW. Comparison of the release of adipokines by adipose tissue, adipose tissue matrix, and adipocytes from visceral and subcutaneous abdominal adipose tissues of obese humans. Endocrinology. 2004; 145(5): 2273-82, CrossRef.

Bing C. Is interleukin-1β a culprit in macrophage-adipocyte crosstalk in obesity? Adipocyte. 2015; 4(2): 149-52, CrossRef.

Reindl-Schwaighofer R, Hödlmoser S, Eskandary F, Poglitsch M, Bonderman D, Strassl R, et al. ACE2 elevation in severe COVID-19. Am J Respir Crit Care Med. 2021; 203(9): 1191-6, CrossRef.

Ziegler CGK, Allon SJ, Nyquist SK, Mbano IM, Miao VN, Tzouanas CN, et al. SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues. Cell. 2020; 181(5): 1016-35.e19, CrossRef.

Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. COVID-19: Consider cytokine storm syndromes and immunosuppression. Lancet. 2020; 395(10229): 1033-4, CrossRef.

Al-Samkari H, Berliner N. Hemophagocytic lymphohistiocytosis. Annu Rev Pathol Mech Dis. 2018; 13(1): 27-49, CrossRef.

Crayne CB, Albeituni S, Nichols KE, Cron RQ. The immunology of macrophage activation syndrome. Front Immunol. 2019; 10: 119, CrossRef.

Nejat R, Sadr AS. Are losartan and imatinib effective against SARS-CoV2 pathogenesis? A pathophysiologic-based in silico study. In Silico Pharmacol. 2020; 9(1): 1. doi: 10.1007/s40203-020-00058-7, CrossRef.

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; 8(11): 1154-8, CrossRef.

Zhang Z, Zeng E, Zhang L, Wang W, Jin Y, Sun J, et al. Potent prophylactic and therapeutic efficacy of recombinant human ACE2-Fc against SARS-CoV-2 infection in vivo. Cell Discov. 2021; 7(1): 65, CrossRef.

Belančić A, Kresović A, Rački V. Potential pathophysiological mechanisms leading to increased COVID-19 susceptibility and severity in obesity. Obes Med. 2020; 19: 100259, CrossRef.

DOI: https://doi.org/10.18585/inabj.v15i5.2552

Copyright (c) 2023 The Prodia Education and Research Institute

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.


Indexed by:






The Prodia Education and Research Institute