Cargando…
SARS-CoV-2 Spike Protein Intensifies Cerebrovascular Complications in Diabetic hACE2 Mice through RAAS and TLR Signaling Activation
Diabetics are more vulnerable to SARS-CoV-2 neurological manifestations. The molecular mechanisms of SARS-CoV-2-induced cerebrovascular dysfunction in diabetes are unclear. We hypothesize that SARS-CoV-2 exacerbates diabetes-induced cerebrovascular oxidative stress and inflammation via activation of...
Autores principales: | , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10671133/ https://www.ncbi.nlm.nih.gov/pubmed/38003584 http://dx.doi.org/10.3390/ijms242216394 |
_version_ | 1785149380149379072 |
---|---|
author | Burnett, Faith N. Coucha, Maha Bolduc, Deanna R. Hermanns, Veronica C. Heath, Stan P. Abdelghani, Maryam Macias-Moriarity, Lilia Z. Abdelsaid, Mohammed |
author_facet | Burnett, Faith N. Coucha, Maha Bolduc, Deanna R. Hermanns, Veronica C. Heath, Stan P. Abdelghani, Maryam Macias-Moriarity, Lilia Z. Abdelsaid, Mohammed |
author_sort | Burnett, Faith N. |
collection | PubMed |
description | Diabetics are more vulnerable to SARS-CoV-2 neurological manifestations. The molecular mechanisms of SARS-CoV-2-induced cerebrovascular dysfunction in diabetes are unclear. We hypothesize that SARS-CoV-2 exacerbates diabetes-induced cerebrovascular oxidative stress and inflammation via activation of the destructive arm of the renin–angiotensin-aldosterone system (RAAS) and Toll-like receptor (TLR) signaling. SARS-CoV-2 spike protein was injected in humanized ACE2 transgenic knock-in mice. Cognitive functions, cerebral blood flow, cerebrovascular architecture, RAAS, and TLR signaling were used to determine the effect of SARS-CoV-2 spike protein in diabetes. Studies were mirrored in vitro using human brain microvascular endothelial cells treated with high glucose-conditioned media to mimic diabetic conditions. Spike protein exacerbated diabetes-induced cerebrovascular oxidative stress, inflammation, and endothelial cell death resulting in an increase in vascular rarefaction and diminished cerebral blood flow. SARS-CoV-2 spike protein worsened cognitive dysfunction in diabetes compared to control mice. Spike protein enhanced the destructive RAAS arm at the expense of the RAAS protective arm. In parallel, spike protein significantly exacerbated TLR signaling in diabetes, aggravating inflammation and cellular apoptosis vicious circle. Our study illustrated that SAR-CoV-2 spike protein intensified RAAS and TLR signaling in diabetes, increasing cerebrovascular damage and cognitive dysfunction. |
format | Online Article Text |
id | pubmed-10671133 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-106711332023-11-16 SARS-CoV-2 Spike Protein Intensifies Cerebrovascular Complications in Diabetic hACE2 Mice through RAAS and TLR Signaling Activation Burnett, Faith N. Coucha, Maha Bolduc, Deanna R. Hermanns, Veronica C. Heath, Stan P. Abdelghani, Maryam Macias-Moriarity, Lilia Z. Abdelsaid, Mohammed Int J Mol Sci Article Diabetics are more vulnerable to SARS-CoV-2 neurological manifestations. The molecular mechanisms of SARS-CoV-2-induced cerebrovascular dysfunction in diabetes are unclear. We hypothesize that SARS-CoV-2 exacerbates diabetes-induced cerebrovascular oxidative stress and inflammation via activation of the destructive arm of the renin–angiotensin-aldosterone system (RAAS) and Toll-like receptor (TLR) signaling. SARS-CoV-2 spike protein was injected in humanized ACE2 transgenic knock-in mice. Cognitive functions, cerebral blood flow, cerebrovascular architecture, RAAS, and TLR signaling were used to determine the effect of SARS-CoV-2 spike protein in diabetes. Studies were mirrored in vitro using human brain microvascular endothelial cells treated with high glucose-conditioned media to mimic diabetic conditions. Spike protein exacerbated diabetes-induced cerebrovascular oxidative stress, inflammation, and endothelial cell death resulting in an increase in vascular rarefaction and diminished cerebral blood flow. SARS-CoV-2 spike protein worsened cognitive dysfunction in diabetes compared to control mice. Spike protein enhanced the destructive RAAS arm at the expense of the RAAS protective arm. In parallel, spike protein significantly exacerbated TLR signaling in diabetes, aggravating inflammation and cellular apoptosis vicious circle. Our study illustrated that SAR-CoV-2 spike protein intensified RAAS and TLR signaling in diabetes, increasing cerebrovascular damage and cognitive dysfunction. MDPI 2023-11-16 /pmc/articles/PMC10671133/ /pubmed/38003584 http://dx.doi.org/10.3390/ijms242216394 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Burnett, Faith N. Coucha, Maha Bolduc, Deanna R. Hermanns, Veronica C. Heath, Stan P. Abdelghani, Maryam Macias-Moriarity, Lilia Z. Abdelsaid, Mohammed SARS-CoV-2 Spike Protein Intensifies Cerebrovascular Complications in Diabetic hACE2 Mice through RAAS and TLR Signaling Activation |
title | SARS-CoV-2 Spike Protein Intensifies Cerebrovascular Complications in Diabetic hACE2 Mice through RAAS and TLR Signaling Activation |
title_full | SARS-CoV-2 Spike Protein Intensifies Cerebrovascular Complications in Diabetic hACE2 Mice through RAAS and TLR Signaling Activation |
title_fullStr | SARS-CoV-2 Spike Protein Intensifies Cerebrovascular Complications in Diabetic hACE2 Mice through RAAS and TLR Signaling Activation |
title_full_unstemmed | SARS-CoV-2 Spike Protein Intensifies Cerebrovascular Complications in Diabetic hACE2 Mice through RAAS and TLR Signaling Activation |
title_short | SARS-CoV-2 Spike Protein Intensifies Cerebrovascular Complications in Diabetic hACE2 Mice through RAAS and TLR Signaling Activation |
title_sort | sars-cov-2 spike protein intensifies cerebrovascular complications in diabetic hace2 mice through raas and tlr signaling activation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10671133/ https://www.ncbi.nlm.nih.gov/pubmed/38003584 http://dx.doi.org/10.3390/ijms242216394 |
work_keys_str_mv | AT burnettfaithn sarscov2spikeproteinintensifiescerebrovascularcomplicationsindiabetichace2micethroughraasandtlrsignalingactivation AT couchamaha sarscov2spikeproteinintensifiescerebrovascularcomplicationsindiabetichace2micethroughraasandtlrsignalingactivation AT bolducdeannar sarscov2spikeproteinintensifiescerebrovascularcomplicationsindiabetichace2micethroughraasandtlrsignalingactivation AT hermannsveronicac sarscov2spikeproteinintensifiescerebrovascularcomplicationsindiabetichace2micethroughraasandtlrsignalingactivation AT heathstanp sarscov2spikeproteinintensifiescerebrovascularcomplicationsindiabetichace2micethroughraasandtlrsignalingactivation AT abdelghanimaryam sarscov2spikeproteinintensifiescerebrovascularcomplicationsindiabetichace2micethroughraasandtlrsignalingactivation AT maciasmoriarityliliaz sarscov2spikeproteinintensifiescerebrovascularcomplicationsindiabetichace2micethroughraasandtlrsignalingactivation AT abdelsaidmohammed sarscov2spikeproteinintensifiescerebrovascularcomplicationsindiabetichace2micethroughraasandtlrsignalingactivation |