Lisinopril increases lung ACE2 levels and SARS-CoV-2 viral load and decreases inflammation but not disease severity in experimental COVID-19.

Autor:	Silva-Santos Y; Laboratory of Malaria Cellular and Molecular Immunopathology, Faculty of Pharmaceutical Sciences, Department of Clinical and Toxicological Analysis, University of São Paulo, São Paulo, Brazil.; Laboratory of Malaria Research, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil., Pagni RL; Immunology Laboratory, Heart Institute, Faculty of Medicine, University of São Paulo, São Paulo, Brazil., Gamon THM; Laboratory of Clinical and Molecular Virology, Institute of Biomedical Sciences, Department of Microbiology, University of São Paulo, São Paulo, Brazil., de Azevedo MSP; Laboratory of Clinical and Molecular Virology, Institute of Biomedical Sciences, Department of Microbiology, University of São Paulo, São Paulo, Brazil.; Laboratory of Experimental Immunoparasitology, Institute of Biomedical Sciences, Department of Parasitology, University of São Paulo, São Paulo, Brazil., Bielavsky M; Laboratory of Malaria Cellular and Molecular Immunopathology, Faculty of Pharmaceutical Sciences, Department of Clinical and Toxicological Analysis, University of São Paulo, São Paulo, Brazil., Darido MLG; Laboratory of Clinical and Molecular Virology, Institute of Biomedical Sciences, Department of Microbiology, University of São Paulo, São Paulo, Brazil., de Oliveira DBL; Laboratory of Clinical and Molecular Virology, Institute of Biomedical Sciences, Department of Microbiology, University of São Paulo, São Paulo, Brazil.; Hospital Israelita Albert Einstein, São Paulo, Brazil., de Souza EE; Unit for Drug Discovery, Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil., Wrenger C; Unit for Drug Discovery, Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil., Durigon EL; Laboratory of Clinical and Molecular Virology, Institute of Biomedical Sciences, Department of Microbiology, University of São Paulo, São Paulo, Brazil., Luvizotto MCR; School of Veterinary Medicine of Araçatuba, São Paulo State University, São Paulo, Brazil., Ackerman HC; Physiology Unit, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, Rockville, MD, United States., Marinho CRF; Laboratory of Experimental Immunoparasitology, Institute of Biomedical Sciences, Department of Parasitology, University of São Paulo, São Paulo, Brazil., Epiphanio S; Laboratory of Malaria Cellular and Molecular Immunopathology, Faculty of Pharmaceutical Sciences, Department of Clinical and Toxicological Analysis, University of São Paulo, São Paulo, Brazil., Carvalho LJM; Laboratory of Malaria Research, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil.
Jazyk:	angličtina
Zdroj:	Frontiers in pharmacology [Front Pharmacol] 2024 Jul 12; Vol. 15, pp. 1414406. Date of Electronic Publication: 2024 Jul 12 (Print Publication: 2024).
DOI:	10.3389/fphar.2024.1414406
Abstrakt:	COVID-19 causes more severe and frequently fatal disease in patients with pre-existing comorbidities such as hypertension and heart disease. SARS-CoV-2 virus enters host cells through the angiotensin-converting enzyme 2 (ACE2), which is fundamental in maintaining arterial pressure through the renin-angiotensin system (RAS). Hypertensive patients commonly use medications such as angiotensin-converting enzyme inhibitors (ACEi), which can modulate the expression of ACE2 and, therefore, potentially impact the susceptibility and severity of SARS-CoV-2 infection. Here we assessed whether treatment of ACE2-humanized (K18-hACE2) mice with the ACEi Lisinopril affects lung ACE2 levels and the outcome of experimental COVID-19. K18-hACE2 mice were treated for 21 days with Lisinopril 10 mg/kg and were then infected with 10 5  PFU of SARS-CoV-2 (Wuhan strain). Body weight, clinical score, respiratory function, survival, lung ACE2 levels, viral load, lung histology, and cytokine (IL-6, IL-33, and TNF-α) levels were assessed. Mice treated with Lisinopril for 21 days showed increased levels of ACE2 in the lungs. Infection with SARS-CoV-2 led to massive decrease in lung ACE2 levels at 3 days post-infection (dpi) in treated and untreated animals, but Lisinopril-treated mice showed a fast recovery (5dpi) of ACE2 levels. Higher ACE2 levels in Lisinopril-treated mice led to remarkably higher lung viral loads at 3 and 6/7dpi. Lisinopril-treated mice showed decreased levels of the pro-inflammatory cytokines IL-6 and TNF-α in the serum and lungs at 6/7dpi. Marginal improvements in body weight, clinical score and survival were observed in Lisinopril-treated mice. No differences between treated and untreated infected mice were observed in respiratory function and lung histology. Lisinopril treatment showed both deleterious (higher viral loads) and beneficial (anti-inflammatory and probably anti-constrictory and anti-coagulant) effects in experimental COVID-19. These effects seem to compensate each other, resulting in marginal beneficial effects in terms of outcome for Lisinopril-treated animals. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision. (Copyright © 2024 Silva-Santos, Pagni, Gamon, de Azevedo, Bielavsky, Darido, de Oliveira, de Souza, Wrenger, Durigon, Luvizotto, Ackerman, Marinho, Epiphanio and Carvalho.)
Databáze:	MEDLINE
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