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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

itochondrial DNA and TLR9 activation contribute to SARS-CoV-2-induced endothelial cell damag

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Author(s):
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Costa, Tiago J. [1, 2] ; Potje, Simone R. [1, 3] ; Fraga-Silva, Thais F. C. [4] ; Da Silva-Neto, Julio A. [1] ; Barros, Paula R. [1] ; Rodrigues, Daniel [1] ; Machado, Mirele R. [1] ; Martins, Ronaldo B. [5] ; Santos-Eichler, Rosangela A. [6] ; Benatti, Maira N. [7] ; de Sa, Keyla S. G. [8] ; Almado, Carlos Eduardo L. [9] ; Castro, Italo A. [5] ; Pontelli, Marjorie C. [5] ; La Serra, Leonardo [5] ; Carneiro, Fernando S. [1] ; Becari, Christiane [10] ; Louzada-Junior, Paulo [7] ; Oliveira, Rene D. R. [7] ; Zamboni, Dario S. [8] ; Arruda, Eurico [5] ; Auxiliadora-Martins, Maria [10] ; Giachini, Fernanda R. C. [9] ; Bonato, Vania L. D. [4] ; Zachara, Natasha E. [2] ; Bomfim, Gisele F. [11] ; Tostes, Rita C. [1]
Total Authors: 27
Affiliation:
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[1] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Pharmacol, Ribeirao Preto, SP - Brazil
[2] Johns Hopkins Univ, Sch Med, Dept Biol Chem, Baltimore, MD 21218 - USA
[3] Minas Gerais State Univ UEMG, Belo Horizonte, MG - Brazil
[4] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Biochem & Immunol, Ribeirao Preto, SP - Brazil
[5] Univ Sao Paulo, Ribeirao Preto Med Sch, Virol Res Ctr, Ribeirao Preto, SP - Brazil
[6] Univ Sao Paulo, Inst Biomed Sci, Dept Pharmacol, Ribeirao Preto, SP - Brazil
[7] Univ Sao Paulo, Dept Clin Med, Div Internal Med, Ribeirao Preto Med Sch, Ribeirao Preto, SP - Brazil
[8] Univ Sao Paulo, Dept Cell & Mol Biol, Ribeirao Preto Med Sch, Ribeirao Preto, SP - Brazil
[9] Fed Univ Mato Grosso UFMT, Inst Biol & Hlth Sci, Cuiaba - Brazil
[10] Univ Sao Paulo, Dept Surg & Anat, Ribeirao Preto Med Sch, Ribeirao Preto, SP - Brazil
[11] Fed Univ Mato Grosso UFMT, Inst Hlth Sci, Cuiaba - Brazil
Total Affiliations: 11
Document type: Journal article
Source: VASCULAR PHARMACOLOGY; v. 142, FEB 2022.
Web of Science Citations: 1
Abstract

Background and purpose: Mitochondria play a central role in the host response to viral infection and immunity, being key to antiviral signaling and exacerbating inflammatory processes. Mitochondria and Toll-like receptor (TLR) have been suggested as potential targets in SARS-CoV-2 infection. However, the involvement of TLR9 in SARS-Cov-2-induced endothelial dysfunction and potential contribution to cardiovascular complications in COVID-19 have not been demonstrated. This study determined whether infection of endothelial cells by SARSCoV-2 affects mitochondrial function and induces mitochondrial DNA (mtDNA) release. We also questioned whether TLR9 signaling mediates the inflammatory responses induced by SARS-CoV-2 in endothelial cells. Experimental approach: Human umbilical vein endothelial cells (HUVECs) were infected by SARS-CoV-2 and immunofluorescence was used to confirm the infection. Mitochondrial function was analyzed by specific probes and mtDNA levels by real-time polymerase chain reaction (RT-PCR). Inflammatory markers were measured by ELISA, protein expression by western blot, intracellular calcium (Ca2+) by FLUOR-4, and vascular reactivity with a myography. Key results: SARS-CoV-2 infected HUVECs, which express ACE2 and TMPRSS2 proteins, and promoted mitochondrial dysfunction, i.e. it increased mitochondria-derived superoxide anion, mitochondrial membrane potential, and mtDNA release, leading to activation of TLR9 and NF-kB, and release of cytokines. SARS-CoV-2 also decreased nitric oxide synthase (eNOS) expression and inhibited Ca2+ responses in endothelial cells. TLR9 blockade reduced SARS-CoV-2-induced IL-6 release and prevented decreased eNOS expression. mtDNA increased vascular reactivity to endothelin-1 (ET-1) in arteries from wild type, but not TLR9 knockout mice. These events were recapitulated in serum samples from COVID-19 patients, that exhibited increased levels of mtDNA compared to sex-and age-matched healthy subjects and patients with comorbidities. Conclusion and applications: SARS-CoV-2 infection impairs mitochondrial function and activates TLR9 signaling in endothelial cells. TLR9 triggers inflammatory responses that lead to endothelial cell dysfunction, potentially contributing to the severity of symptoms in COVID-19. Targeting mitochondrial metabolic pathways may help to define novel therapeutic strategies for COVID-19. (AU)

FAPESP's process: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases
Grantee:Fernando de Queiroz Cunha
Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
FAPESP's process: 16/21239-0 - Structure of caveolae and its modulation on glycocalyx and the mechanotransducer process in essential hypertension
Grantee:Simone Regina Potje
Support Opportunities: Scholarships in Brazil - Post-Doctoral
FAPESP's process: 17/25116-2 - Role of O-GlcNacylation (O-GlcNAc) on the expression and function of classical estrogen receptor alpha (ERa66kDa) and splice variant of estrogen receptor alpha (ERa36kDa) in the common carotid artery of aging mice
Grantee:Tiago Januário da Costa
Support Opportunities: Scholarships in Brazil - Post-Doctoral