{"doi":"10.1101/2021.02.14.431174","title":"Direct activation of endothelial cells by SARS-CoV-2 nucleocapsid protein is blocked by Simvastatin","abstract":"Emerging evidence suggests that endothelial activation plays a central role in the pathogenesis of acute respiratory distress syndrome (ARDS) and multi-organ failure in patients with COVID-19. However, the molecular mechanisms underlying endothelial activation in COVID-19 patients remain unclear. In this study, the SARS-CoV-2 viral proteins that potently activate human endothelial cells were screened to elucidate the molecular mechanisms involved with endothelial activation. It was found that nucleocapsid protein (NP) of SARS-CoV-2 significantly activated human endothelial cells through TLR2/NF-κB and MAPK signaling pathways. Moreover, by screening a natural microbial compound library containing 154 natural compounds, simvastatin was identified as a potent inhibitor of NP-induced endothelial activation. Remarkablely, though the protein sequences of N proteins from coronaviruses are highly conserved, only NP from SARS-CoV-2 induced endothelial activation. The NPs from other coronaviruses such as SARS-CoV, MERS-CoV, HUB1-CoV and influenza virus H1N1 did not affect endothelial activation. These findings are well consistent with the results from clinical investigations showing broad endotheliitis and organ injury in severe COVID-19 patients. In conclusion, the study provides insights on SARS-CoV-2-induced vasculopathy and coagulopathy, and suggests that simvastatin, an FDA-approved lipid-lowering drug, may benefit to prevent the pathogenesis and improve the outcome of COVID-19 patients.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":213951,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":13,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9643,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":639617,"name":"Tianhua Lei","orcid":null,"position":1,"is_corresponding":false},{"id":718983,"name":"Parth Patel","orcid":"0000-0002-3113-2546","position":2,"is_corresponding":false},{"id":806690,"name":"Chi H Lee","orcid":"0000-0001-7014-3822","position":3,"is_corresponding":false},{"id":807371,"name":"Paula Monaghan‐Nichols","orcid":null,"position":4,"is_corresponding":false},{"id":566274,"name":"Hongbo Xin","orcid":"0000-0002-2143-5092","position":5,"is_corresponding":false},{"id":321300,"name":"Jianming Qiu","orcid":"0000-0001-9850-1695","position":6,"is_corresponding":false},{"id":376178,"name":"Mingui Fu","orcid":"0000-0001-6315-8372","position":7,"is_corresponding":false},{"id":806689,"name":"Yisong Qian","orcid":"0000-0001-6251-6756","position":0,"is_corresponding":true}],"reference_count":46,"raw_metadata":null,"created_at":"2026-07-18T23:52:41.672172Z","pmid":"33594363","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}