{"doi":"10.1161/circulationaha.120.049844","title":"Unfolded Protein Response as a Compensatory Mechanism and Potential Therapeutic Target in PLN R14del Cardiomyopathy","abstract":"BACKGROUND: Phospholamban (PLN) is a critical regulator of calcium cycling and contractility in the heart. The loss of arginine at position 14 in PLN (R14del) is associated with dilated cardiomyopathy with a high prevalence of ventricular arrhythmias. How the R14 deletion causes dilated cardiomyopathy is poorly understood, and there are no disease-specific therapies. METHODS: We used single-cell RNA sequencing to uncover PLN R14del disease mechanisms in human induced pluripotent stem cells (hiPSC-CMs). We used both 2-dimensional and 3-dimensional functional contractility assays to evaluate the impact of modulating disease-relevant pathways in PLN R14del hiPSC-CMs. RESULTS: Modeling of the PLN R14del cardiomyopathy with isogenic pairs of hiPSC-CMs recapitulated the contractile deficit associated with the disease in vitro. Single-cell RNA sequencing revealed the induction of the unfolded protein response (UPR) pathway in PLN R14del compared with isogenic control hiPSC-CMs. The activation of UPR was also evident in the hearts from PLN R14del patients. Silencing of each of the 3 main UPR signaling branches (IRE1, ATF6, or PERK) by siRNA exacerbated the contractile dysfunction of PLN R14del hiPSC-CMs. We explored the therapeutic potential of activating the UPR with a small molecule activator, BiP (binding immunoglobulin protein) inducer X. PLN R14del hiPSC-CMs treated with BiP protein inducer X showed a dose-dependent amelioration of the contractility deficit in both 2-dimensional cultures and 3-dimensional engineered heart tissues without affecting calcium homeostasis. CONCLUSIONS: Together, these findings suggest that the UPR exerts a protective effect in the setting of PLN R14del cardiomyopathy and that modulation of the UPR might be exploited therapeutically.","journal":"Circulation","year":2021,"id":152294,"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":76,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9421,"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":646642,"name":"Isaac Perea‐Gil","orcid":"0000-0002-9741-428X","position":1,"is_corresponding":false},{"id":229035,"name":"Renée G. C. Maas","orcid":"0000-0002-6607-4104","position":2,"is_corresponding":false},{"id":469972,"name":"Magdaléna Harakaľová","orcid":"0000-0002-7293-1029","position":3,"is_corresponding":false},{"id":646643,"name":"Alexandra A. Gavidia","orcid":"0000-0002-9347-4664","position":4,"is_corresponding":false},{"id":352639,"name":"Jennifer Arthur Ataam","orcid":"0000-0002-6781-9892","position":5,"is_corresponding":false},{"id":74135,"name":"Ting-Hsuan Wu","orcid":"0000-0002-6869-362X","position":6,"is_corresponding":false},{"id":469981,"name":"Aryan Vink","orcid":"0000-0002-9371-8788","position":7,"is_corresponding":false},{"id":470691,"name":"Jiayi Pei","orcid":null,"position":8,"is_corresponding":false},{"id":646644,"name":"Nirmal Vadgama","orcid":"0000-0001-6226-3867","position":9,"is_corresponding":false},{"id":287880,"name":"Albert J.H. Suurmeijer","orcid":"0000-0003-1361-9454","position":10,"is_corresponding":false},{"id":619125,"name":"Wouter P. te Rijdt","orcid":"0000-0003-4852-9379","position":11,"is_corresponding":false},{"id":229031,"name":"Michelle M. Vu","orcid":"0000-0003-1605-3548","position":12,"is_corresponding":false},{"id":229032,"name":"Prashila Amatya","orcid":"0000-0002-9182-0279","position":13,"is_corresponding":false},{"id":319197,"name":"Maricela Prado","orcid":null,"position":14,"is_corresponding":false},{"id":523582,"name":"Yuan Zhang","orcid":"0000-0002-3390-3797","position":15,"is_corresponding":false},{"id":583018,"name":"Logan Dunkenberger","orcid":null,"position":16,"is_corresponding":false},{"id":241161,"name":"Joost P. G. Sluijter","orcid":"0000-0003-2088-9102","position":17,"is_corresponding":false},{"id":278897,"name":"Karim Sallam","orcid":"0000-0003-3469-6571","position":18,"is_corresponding":false},{"id":21948,"name":"Folkert W. Asselbergs","orcid":"0000-0002-1692-8669","position":19,"is_corresponding":false},{"id":229040,"name":"Mark Mercola","orcid":"0000-0002-1430-2013","position":20,"is_corresponding":false},{"id":305677,"name":"Ioannis Karakikes","orcid":"0000-0002-4348-600X","position":21,"is_corresponding":false},{"id":229959,"name":"Dries Feyen","orcid":null,"position":0,"is_corresponding":true}],"reference_count":51,"raw_metadata":null,"created_at":"2026-07-18T23:43:22.562252Z","pmid":"33928785","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":[]}