{"doi":"10.1093/cvr/cvab027","title":"Krüppel-like factor 14 deletion in myeloid cells accelerates atherosclerotic lesion development","abstract":"AIMS: Atherosclerosis is the dominant pathologic basis of many cardiovascular diseases. Large genome-wide association studies have identified that single-nucleotide polymorphisms proximal to Krüppel-like factor 14 (KLF14), a member of the zinc finger family of transcription factors, are associated with higher cardiovascular risks. Macrophage dysfunction contributes to atherosclerosis development and has been recognized as a potential therapeutic target for treating many cardiovascular diseases. Herein, we address the biologic function of KLF14 in macrophages and its role during the development of atherosclerosis. METHODS AND RESULTS: KLF14 expression was markedly decreased in cholesterol loaded foam cells, and overexpression of KLF14 significantly increased cholesterol efflux and inhibited the inflammatory response in macrophages. We generated myeloid cell-selective Klf14 knockout (Klf14LysM) mice in the ApoE-/- background for the atherosclerosis study. Klf14LysMApoE-/- and litter-mate control mice (Klf14fl/flApoE-/-) were placed on the Western Diet for 12 weeks to induce atherosclerosis. Macrophage Klf14 deficiency resulted in increased atherosclerosis development without affecting the plasma lipid profiles. Klf14-deficient peritoneal macrophages showed significantly reduced cholesterol efflux resulting in increased lipid accumulation and exacerbated inflammatory response. Mechanistically, KLF14 upregulates the expression of a key cholesterol efflux transporter, ABCA1 (ATP-binding cassette transporter A1), while it suppresses the expression of several critical components of the inflammatory cascade. In macrophages, activation of KLF14 by its activator, perhexiline, a drug clinically used to treat angina, significantly inhibited the inflammatory response and increased cholesterol efflux in a KLF14-dependent manner in macrophages without triggering hepatic lipogenesis. CONCLUSIONS: This study provides insights into the anti-atherosclerotic effects of myeloid KLF14 through promoting cholesterol efflux and suppressing the inflammatory response. Activation of KLF14 may represent a potential new therapeutic approach to prevent or treat atherosclerosis.","journal":"Cardiovascular Research","year":2021,"id":170630,"datarank":0.5050943744979712,"base_score":3.367295829986474,"endowment":3.367295829986474,"self_citation_contribution":0.5050943744979712,"citation_network_contribution":0.0,"self_endowment_contribution":0.5050943744979712,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":28,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9556,"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":243095,"name":"Yanhong Guo","orcid":"0000-0002-3334-9159","position":1,"is_corresponding":false},{"id":243091,"name":"Haocheng Lu","orcid":"0000-0002-5740-8010","position":2,"is_corresponding":false},{"id":672652,"name":"Yonghong Luo","orcid":"0000-0001-8996-9253","position":3,"is_corresponding":false},{"id":420617,"name":"Wenting Hu","orcid":"0000-0003-4639-9056","position":4,"is_corresponding":false},{"id":471094,"name":"Wenying Liang","orcid":"0000-0001-9985-6674","position":5,"is_corresponding":false},{"id":243096,"name":"Minerva T. Garcia-Barrio","orcid":"0000-0002-3381-3847","position":6,"is_corresponding":false},{"id":243094,"name":"Lin Chang","orcid":"0000-0002-5621-8426","position":7,"is_corresponding":false},{"id":298046,"name":"Anna Schwendeman","orcid":"0000-0002-8023-8080","position":8,"is_corresponding":false},{"id":243097,"name":"Jifeng Zhang","orcid":"0000-0001-5161-4705","position":9,"is_corresponding":false},{"id":237553,"name":"Y. Eugene Chen","orcid":"0000-0003-2357-7825","position":10,"is_corresponding":false},{"id":357093,"name":"Huilun Wang","orcid":"0000-0002-0583-1386","position":0,"is_corresponding":true}],"reference_count":70,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:46:24.040760Z","pmid":"33538785","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":[]}