{"doi":"10.1016/j.ijcard.2014.06.062","title":"Increased concentration of circulating angiogenesis and nitric oxide inhibitors induces endothelial to mesenchymal transition and myocardial fibrosis in patients with chronic kidney disease","abstract":null,"journal":"International Journal of Cardiology","year":2014,"id":690279,"datarank":0.6907755278982138,"base_score":4.605170185988092,"endowment":4.605170185988092,"self_citation_contribution":0.6907755278982138,"citation_network_contribution":0.0,"self_endowment_contribution":0.6907755278982138,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":99,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1803414,"name":"Robert Padera","orcid":null,"position":1,"is_corresponding":false},{"id":1803415,"name":"Alexander M. Helfand","orcid":"0000-0002-8733-573X","position":2,"is_corresponding":false},{"id":235978,"name":"Michael Zeisberg","orcid":"0000-0001-5826-738X","position":3,"is_corresponding":false},{"id":1142379,"name":"Xingbo Xu","orcid":"0000-0002-8249-5507","position":4,"is_corresponding":false},{"id":447300,"name":"Xiaopeng Liu","orcid":"0000-0001-9856-0150","position":5,"is_corresponding":false},{"id":54241,"name":"Jonathan Himmelfarb","orcid":"0000-0002-3319-1224","position":6,"is_corresponding":false},{"id":662671,"name":"Angeles Cinelli","orcid":null,"position":7,"is_corresponding":false},{"id":104298,"name":"Raghu Kalluri","orcid":"0000-0002-2190-547X","position":8,"is_corresponding":false},{"id":1803416,"name":"Elisabeth M. Zeisberg","orcid":null,"position":9,"is_corresponding":false},{"id":255774,"name":"David M. Charytan","orcid":"0000-0002-3368-247X","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Increased concentration of circulating angiogenesis and nitric oxide inhibitors induces endothelial to mesenchymal transition and myocardial fibrosis in patients with chronic kidney disease","abstract":"<h4>Background</h4>Sudden cardiovascular death is increased in chronic kidney disease (CKD). Experimental CKD models suggest that angiogenesis and nitric oxide (NO) inhibitors induce myocardial fibrosis and microvascular dropout thereby facilitating arrhythmogenesis. We undertook this study to characterize associations of CKD with human myocardial pathology, NO-related circulating angiogenesis inhibitors, and endothelial cell behavior.<h4>Methods</h4>We compared heart (n=54) and serum (n=162) samples from individuals with and without CKD, and assessed effects of serum on human coronary artery endothelial cells (HCAECs) in vitro. Left ventricular fibrosis and capillary density were quantified in post-mortem samples. Endothelial to mesenchymal transition (EndMT) was assessed by immunostaining of post-mortem samples and RNA expression in heart tissue obtained during cardiac surgery. Circulating asymmetric dimethylarginine (ADMA), endostatin (END), angiopoietin-2 (ANG), and thrombospondin-2 (TSP) were measured, and the effect of these factors and of subject serum on proliferation, apoptosis, and EndMT of HCAEC was analyzed.<h4>Results</h4>Cardiac fibrosis increased 12% and 77% in stage 3-4 CKD and ESRD and microvascular density decreased 12% and 16% vs. preserved renal function. EndMT-derived fibroblast proportion was 17% higher in stage 3-4 CKD and ESRD (P trend = 0.02). ADMA, ANG, TSP, and END concentrations increased in CKD. Both individual factors and CKD serum increased HCAEC apoptosis (P=0.02), decreased proliferation (P=0.03), and induced EndMT.<h4>Conclusions</h4>CKD is associated with an increase in circulating angiogenesis and NO inhibitors, which impact proliferation and apoptosis of cardiac endothelial cells and promote EndMT, leading to cardiac fibrosis and capillary rarefaction. These processes may play key roles in CKD-associated CV disease.","is_dataset_classified":null,"base_score":4.605170185988092,"endowment":4.605170185988092,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"25049013","pmcid":"PMC4161362","openalex_id":"https://openalex.org/W2023882694","authors":[],"funders":[{"funder_name":"NIDDK NIH HHS","grant_id":"DK081576","title":null},{"funder_name":"NIDDK NIH HHS","grant_id":"R01 DK081576","title":null},{"funder_name":"NCI NIH HHS","grant_id":"CA163191","title":null},{"funder_name":"NCI NIH HHS","grant_id":"CA151925","title":null},{"funder_name":"NCI NIH HHS","grant_id":"R01 CA125550","title":null},{"funder_name":"NIDDK NIH HHS","grant_id":"DK055001","title":null},{"funder_name":"NCI NIH HHS","grant_id":"U54 CA163191","title":null},{"funder_name":"NIDDK NIH HHS","grant_id":"R01 DK055001","title":null},{"funder_name":"NCI NIH HHS","grant_id":"CA125550","title":null},{"funder_name":"NCI NIH HHS","grant_id":"R01 CA155370","title":null},{"funder_name":"NCI NIH HHS","grant_id":"CA155370","title":null},{"funder_name":"NCI NIH HHS","grant_id":"P30 CA016672","title":null},{"funder_name":"NHLBI NIH HHS","grant_id":"R01 HL070938","title":null},{"funder_name":"NCI NIH HHS","grant_id":"U01 CA151925","title":null}],"total_grants":14,"fwci":2.9866,"citation_percentile":0.91857814,"influential_citations":0,"citation_trend":[{"year":2015,"count":5},{"year":2016,"count":10},{"year":2017,"count":8},{"year":2018,"count":11},{"year":2019,"count":10},{"year":2020,"count":15},{"year":2021,"count":11},{"year":2022,"count":6},{"year":2023,"count":16},{"year":2024,"count":3},{"year":2025,"count":3},{"year":2026,"count":1}],"oa_status":"green","license":"https://www.elsevier.com/tdm/userlicense/1.0/","oa_locations":[{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/4161362","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/4161362","host_type":"repository"},{"url":"https://api.elsevier.com/content/article/PII:S0167527314011498?httpAccept=text/xml","host_type":"publisher"},{"url":"https://api.elsevier.com/content/article/PII:S0167527314011498?httpAccept=text/plain","host_type":"publisher"},{"url":"https://doi.org/10.1016/j.ijcard.2014.06.062","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/25049013","host_type":"repository"}],"fields_of_study":["Angiogenesis and VEGF in Cancer","Cardiac Fibrosis and Remodeling","Chronic Kidney Disease and Diabetes","Adult","Aged","Aged, 80 and over","Angiogenesis Inhibitors","Biomarkers","Cells, Cultured","Cohort Studies","Endothelium, Vascular","Epithelial-Mesenchymal Transition","Female","Humans","Male","Middle Aged","Nitric Oxide","Renal Insufficiency, Chronic"],"mesh_terms":["Adult","Aged","Aged, 80 and over","Cells, Cultured","Endothelium, Vascular","Female","Humans","Male","Middle Aged","Nitric Oxide","Cohort Studies","Biomarkers","Angiogenesis Inhibitors","Renal Insufficiency, Chronic","Epithelial-Mesenchymal Transition"],"keywords":["Medicine","Angiogenesis","Internal medicine","Fibrosis","Kidney disease","Cardiac fibrosis","Endocrinology","Nitric oxide","Myocardial fibrosis","Cardiology","Cardiovascular disease","angiogenesis inhibitor","Esrd","Ckd","Endothelial To Mesenchymal Transition"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-23T13:26:32.663879Z","pmid":null,"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":[]}