{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T00:08:18Z","timestamp":1792714098128,"version":"4.5.0"},"reference-count":63,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,9,20]],"date-time":"2021-09-20T00:00:00Z","timestamp":1632096000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100013302","name":"King Abdullah International Medical Research Center","doi-asserted-by":"publisher","award":["RC20\/153\/R, 2020, RC18\/171\/R"],"award-info":[{"award-number":["RC20\/153\/R, 2020, RC18\/171\/R"]}],"id":[{"id":"10.13039\/501100013302","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>A purified spike (S) glycoprotein of severe acute respiratory syndrome-related coronavirus 2 (SARS<jats:italic>-<\/jats:italic>CoV<jats:italic>-<\/jats:italic>2) coronavirus was used to study its effects on THP-1 macrophages, peripheral blood mononuclear cells (PBMCs), and HUVEC cells. The S protein mediates the entry of SARS-CoV-2 into cells through binding to the angiotensin-converting enzyme 2 (ACE2) receptors. We measured the viability, intracellular cytokine release, oxidative stress, proinflammatory markers, and THP-1-like macrophage polarization. We observed an increase in apoptosis, ROS generation, MCP-1, and intracellular calcium expression in the THP-1 macrophages. Stimulation with the S protein polarizes the THP-1 macrophages towards proinflammatory futures with an increase in the TNF\u03b1 and MHC-II M1-like phenotype markers. Treating the cells with an ACE inhibitor, perindopril, at 100 \u00b5M reduced apoptosis, ROS, and MHC-II expression induced by S protein. We analyzed the sensitivity of the HUVEC cells after the exposure to a conditioned media (CM) of THP-1 macrophages stimulated with the S protein. The CM induced endothelial cell apoptosis and MCP-1 expression. Treatment with perindopril reduced these effects. However, the direct stimulation of the HUVEC cells with the S protein, slightly increased HIF1\u03b1 and MCP-1 expression, which was significantly increased by the ACE inhibitor treatment. The S protein stimulation induced ROS generation and changed the mitogenic responses of the PBMCs through the upregulation of TNF\u03b1 and interleukin (IL)-17 cytokine expression. These effects were reduced by the perindopril (100 \u00b5M) treatment. Proteomic analysis of the S protein stimulated THP-1 macrophages with or without perindopril (100 \u00b5M) exposed more than 400 differentially regulated proteins. Our results provide a mechanistic analysis suggesting that the blood and vascular components could be activated directly through S protein systemically present in the circulation and that the activation of the local renin angiotensin system may be partially involved in this process.<\/jats:p><jats:sec><jats:title>Graphical<\/jats:title><jats:p>Suggested pathways that might be involved at least in part in S protein inducing activation of inflammatory markers (red narrow) and angiotensin-converting enzyme inhibitor (ACEi) modulation of this process (green narrow).<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2021.728896","type":"journal-article","created":{"date-parts":[[2021,9,20]],"date-time":"2021-09-20T06:41:36Z","timestamp":1632120096000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":79,"title":["SARS-CoV-2 Coronavirus Spike Protein-Induced Apoptosis, Inflammatory, and Oxidative Stress Responses in THP-1-Like-Macrophages: Potential Role of Angiotensin-Converting Enzyme Inhibitor (Perindopril)"],"prefix":"10.3389","volume":"12","author":[{"given":"Tlili","family":"Barhoumi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bandar","family":"Alghanem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hayat","family":"Shaibah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatmah A.","family":"Mansour","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hassan S.","family":"Alamri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maaged A.","family":"Akiel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fayhan","family":"Alroqi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad","family":"Boudjelal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,9,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.35772\/ghm.2020.01016","article-title":"The COVID-19 Pandemic Preparedness or Lack Thereof: From China to Italy","volume":"2","author":"Villa","year":"2020","journal-title":"Glob Health Med"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)30628-0","article-title":"COVID-19: Consider Cytokine Storm Syndromes and Immunosuppression","volume":"395","author":"Mehta","year":"2020","journal-title":"Lancet"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(13)61048-X","article-title":"Adult Haemophagocytic Syndrome","volume":"383","author":"Ramos-Casals","year":"2014","journal-title":"Lancet"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.abe4782","article-title":"Severely Ill COVID-19 Patients Display Impaired Exhaustion Features in SARS-CoV-2-Reactive CD8(+) T Cells","volume":"6","author":"Kusnadi","year":"2021","journal-title":"Sci Immunol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1016\/j.ajpath.2020.08.009","article-title":"Immunopathology of Hyperinflammation in COVID-19","volume":"191","author":"Gustine","year":"2021","journal-title":"Am J Pathol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1002\/path.1570","article-title":"Tissue Distribution of ACE2 Protein, the Functional Receptor for SARS Coronavirus. 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