{"doi":"10.1063/5.0167440","title":"PCSK9 activation promotes early atherosclerosis in a vascular microphysiological system","abstract":"Atherosclerosis is a primary precursor of cardiovascular disease (CVD), the leading cause of death worldwide. While proprotein convertase subtilisin/kexin 9 (PCSK9) contributes to CVD by degrading low-density lipoprotein receptors (LDLR) and altering lipid metabolism, PCSK9 also influences vascular inflammation, further promoting atherosclerosis. Here, we utilized a vascular microphysiological system to test the effect of PCSK9 activation or repression on the initiation of atherosclerosis and to screen the efficacy of a small molecule PCSK9 inhibitor. We have generated PCSK9 over-expressed (P+) or repressed (P-) human induced pluripotent stem cells (iPSCs) and further differentiated them to smooth muscle cells (viSMCs) or endothelial cells (viECs). Tissue-engineered blood vessels (TEBVs) made from P+ viSMCs and viECs resulted in increased monocyte adhesion compared to the wild type (WT) or P- equivalents when treated with enzyme-modified LDL (eLDL) and TNF-α. We also found significant viEC dysfunction, such as increased secretion of VCAM-1, TNF-α, and IL-6, in P+ viECs treated with eLDL and TNF-α. A small molecule compound, NYX-1492, that was originally designed to block PCSK9 binding with the LDLR was tested in TEBVs to determine its effect on lowering PCSK9-induced inflammation. The compound reduced monocyte adhesion in P+ TEBVs with evidence of lowering secretion of VCAM-1 and TNF-α. These results suggest that PCSK9 inhibition may decrease vascular inflammation in addition to lowering plasma LDL levels, enhancing its anti-atherosclerotic effects, particularly in patients with elevated chronic inflammation.","journal":"APL Bioengineering","year":2023,"id":346888,"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":12,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9607,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1087800,"name":"Kevin L. Shores","orcid":"0000-0002-6205-8318","position":1,"is_corresponding":false},{"id":284417,"name":"Jason J. Breithaupt","orcid":"0000-0002-6843-6586","position":2,"is_corresponding":false},{"id":286051,"name":"Caleb S. Lee","orcid":"0000-0001-7291-3229","position":3,"is_corresponding":false},{"id":1042830,"name":"Daniella M. Fodera","orcid":"0000-0002-6162-8761","position":4,"is_corresponding":false},{"id":324729,"name":"Jennifer B. Kwon","orcid":null,"position":5,"is_corresponding":false},{"id":323423,"name":"Adarsh R. Ettyreddy","orcid":"0009-0001-6853-0871","position":6,"is_corresponding":false},{"id":568462,"name":"Kristin M. Myers","orcid":"0000-0002-5989-0242","position":7,"is_corresponding":false},{"id":1087801,"name":"Benny J. Evison","orcid":"0000-0001-5477-8721","position":8,"is_corresponding":false},{"id":1087802,"name":"Alexandra K. Suchowerska","orcid":"0000-0001-5651-3639","position":9,"is_corresponding":false},{"id":29946,"name":"Charles A. Gersbach","orcid":"0000-0003-1478-4013","position":10,"is_corresponding":false},{"id":235103,"name":"Kam W. Leong","orcid":"0000-0002-8133-4955","position":11,"is_corresponding":false},{"id":283946,"name":"George A. Truskey","orcid":"0000-0002-6885-4489","position":12,"is_corresponding":false},{"id":1087799,"name":"Joung-Hyun Lee","orcid":"0000-0002-4275-5343","position":0,"is_corresponding":true}],"reference_count":70,"raw_metadata":null,"created_at":"2026-07-19T01:11:53.085356Z","pmid":"37854060","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":[]}