ENDOTHELIAL INFLAMMATION AND DYSFUNCTION INDUCED BY SARS-COV-2 SPIKE PROTEIN 1 INVOLVE ADAM17 AND INTERFERON ACTIVATION PATHWAYS
Journal of Hypertension
; 41:e88, 2023.
Article
in English
| EMBASE | ID: covidwho-2244622
ABSTRACT
Objective:
COVID19 is associated with vascular inflammation. IFN-alpha (IFNa) and IFN-lambda3 (IFNl3) are potent cytokines produced in viral infections. Their effects involve interferon-stimulated genes (ISGs) and may influence expression of angiotensin-converting enzyme 2 (ACE2), the receptor for S-protein (S1P) of SARS-CoV-2. We hypothesized that S1P-induced immune/inflammatory responses in endothelial cells (EC) are mediated via IFN-activated pathways Design andmethods:
Human ECs were stimulated with S1P (1 mg/mL), IFNa (100ng/mL) or IFNl3 (100IU/mL). Because ACE2, ADAM17 and TMPRSS2 are important for SARS-CoV-2 infection, we used inhibitors of ADAM17 (marimastat, 3.8 nM), ACE2 (MLN4760, 440pM), and TMPRSS2 (camostat, 50 mM). Gene and protein expression was investigated by real-time PCR and immunoblotting, respectively. Vascular function was assessed in mesenteric arteries from wild-type (WT) normotensive and hypertensive (LinA3) mice and in ISG15-deficient (ISG15KO) mice.Results:
S1P increased expression of IFNa (3-fold), IFNl3 (4-fold) and ISGs (2-fold) in EC (p < 0.05). EC responses to IFNa (ISG15 16-fold) were greater than to IFNl3 (ISG15 1.7-fold) (p < 0.05). S1P increased gene expression of IL-6 (1.3-fold), TNFa (6.2-fold) and IL-1b (3.3-fold), effects that were amplified by IFNs. Only the ADAM17 inhibitor marimastat inhibited S1P effects. IFNa and IFNl3 increase protein expression of ADAM17 (27%) and TMPRSS2 (38%). No changes were observed on ACE2 expression. This was associated with increased phosphorylation of Stat1 (134%), Stat2 (102%), ERK1/2 (42%). EC production of IL-6 was increased by IFNa (1,230pg/mL) and IFNl3 (1,124pg/mL) vs control (591pg/mL). Nitric oxide generation and eNOS phosphorylation (Ser1177) were reduced by IFNa (40%) and IFNl3 (40%). Vascular functional responses demonstrated that endothelium-dependent vasorelaxation (% Emax) in vessels from WT-mice stimulated with IFNa (67%) and IFNl3 (71%) were reduced vs control (82%) (p < 0.05). Responses were not altered in vessels from ISG15KO mice. Increased contraction was observed only in vessels from hypertensive mice treated with IFNa (9.1 ± 0.5mN vs control 7.3 ± 0.3mN) (p < 0.05).Conclusions:
In ECs, S1P, IFNa and IFNl3 increased ISG15 and IL-6 by mechanisms dependent on ADAM17. IFNs amplifies endothelial cell inflammatory responses and induced vascular dysfunction through ISG15-dependent mechanisms, with augmented effects in hypertension. Our findings demonstrate that S1P induces immune/inflammatory responses that may be important in endotheliitis associated with COVID-19. This may be especially important in the presence of cardiovascular risk factors, including hypertension.
alpha interferon; endogenous compound; endothelial nitric oxide synthase; interferon; interleukin 1beta; interleukin 28B; interleukin 6; marimastat; mitogen activated protein kinase 1; mitogen activated protein kinase 3; nitric oxide; sphingosine 1 phosphate; STAT1 protein; STAT2 protein; transmembrane protease serine 2; tumor necrosis factor; tumor necrosis factor alpha converting enzyme; virus spike protein; animal cell; animal experiment; animal model; cardiovascular risk factor; conference abstract; controlled study; coronavirus disease 2019; endotheliitis; endothelium cell; gene amplification; gene expression; human; hypertension; immune response; immunoblotting; inflammation; knockout mouse; male; mesenteric artery; mouse; nonhuman; protein expression; protein function; protein phosphorylation; real time polymerase chain reaction; Severe acute respiratory syndrome coronavirus 2; signal transduction; vasodilatation; wild type
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Collection:
Databases of international organizations
Database:
EMBASE
Language:
English
Journal:
Journal of Hypertension
Year:
2023
Document Type:
Article
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