{"doi":"10.1002/ctm2.1017","title":"3′UTR shortening of profibrotic genes and reversibility of fibrosis in patients with end‐stage right ventricular failure","abstract":"Dear Editor, Cardiac fibrosis, a prominent feature of pressure overloaded right ventricle (RV) in pulmonary hypertension (PH), is fundamental to the development of right ventricle failure (RVF). The molecular mechanisms driving fibrosis is not well understood especially at the level of RNA regulation. We found that a defect in alternative polyadenylation (APA) of profibrotic genes is a driving factor that induces fibrosis. Oxidative stress-mediated reactive aldehydes, such as 4-hydroxy-2-nonenal (4HNE) contribute to fibrosis and extracellular matrix (ECM) remodelling. However, their role in APA is unknown. For the first time, our study identified the missing link between 4HNE-mediated stress and the regulation of 3′UTR by APA in the progression of cardiac fibrosis using end-stage RVF specimens. We established a pronounced fibrosis state in RVF compared to the controls (Figure S1A). We assessed the relative distal Poly-A site (dPAS) usage in these samples (Figure S1B). COL1A, FN1 and TGFβR1 showed significantly lesser usage of dPAS and hence, a shortening in their 3′UTR length in RVF (Figure S1C). Due to 3′UTR shortening in profibrotic genes, they lose microRNA (miRNA) or long non-coding RNA (lncRNA) regulatory sites, thus promoting RNA stability, protein expression, and as a consequence, ECM accumulation.1 Finally, we validated the increased protein expression of these 3′UTR shortened genes, COL1A and FN1, in overall RVF tissues and Vimentin-positive fibroblasts (Figure S1D–G). Previous studies have shown 4HNE as a contributor to various pathologies such as LV hypertrophy, PH-induced RV fibrosis, remodelling, myocardial infarction-induced lipid peroxidation, dilated cardiomyopathy and cardiotoxicity.2 We showed a substantial decrease in the expression and activity of aldehyde dehydrogenase 2 (ALDH2), an enzyme metabolizing 4HNE, (Figure S2A–C) and a significant accumulation of 4HNE adducts (Figure S2D and E) in cardiomyocytes and fibroblasts in RVF. Stress was shown to cause global 3′UTR shortening in proliferating and differentiating cells.3 Here, our study provides the first evidence that establishes strong association between 4HNE-mediated stress and its contribution to fibrosis through 3′UTR shortening in profibrotic genes. Fibrosis is mainly enforced by activating cardiac fibroblasts into proliferative α-SMA-positive myofibroblasts, which cause excessive collagen secretion in the ECM. We characterized the fibroblasts isolated from RVF and showed their profibrotic nature (Figure 1). We showed significant shortening in 3′UTR of major ECM genes, such as COL1A and FN1. Additionally, 3′UTRs of TGF-β1 and its receptor TGFβR1 and NFκB, a transcription factor regulating proinflammatory and profibrotic responses which is also implicated in oxidative stress, were also shortened in RVF (Figure 1B). The shortening in these major profibrotic genes correlated with their higher protein expression in RVF fibroblasts (Figure 1C). Further, they were marked by α-SMA, showed accumulation of COL3A and had higher contractility (Figure 1C–F). We demonstrated ALDH2 deficiency and its reduced catalytic activity (Figure 2A–C) leading to 4HNE adduction (Figure 2D and E) and increased intracellular superoxide accumulation (Figure 2F–H) in these profibrotic RVF fibroblasts. Lipid peroxidation and 4HNE accumulation are well-established in fibrosis progression.4 Previous studies show a positive correlation between 4HNE adducts, fibrosis and TGF-β1 expression. Most importantly, it has been directly shown to induce fibrosis by regulating TGF-β1 through its regulator-activator protein-1 (AP-1) and activating NFκB signalling.5 Here, we showed a possible role of 4HNE in 3′UTR regulation of profibrotic genes, including TGF-β1, its receptor TGFβR1, and NFκB in the stressed RVF fibroblasts. Stress was shown to induce global 3′UTR shortening,3 so 4HNE-mediated oxidative stress may induce 3′UTR shortening in profibrotic genes by regulating core APA machinery pro","journal":"Clinical and Translational Medicine","year":2022,"id":287652,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9541,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":938924,"name":"Katarzyna A. Cieslik","orcid":"0000-0002-2167-7921","position":1,"is_corresponding":false},{"id":732902,"name":"Keith A. Youker","orcid":"0000-0003-2535-7973","position":2,"is_corresponding":false},{"id":438210,"name":"Suresh S. Palaniyandi","orcid":"0000-0001-7559-8041","position":3,"is_corresponding":false},{"id":748196,"name":"Ashrith Guha","orcid":"0000-0002-7246-9508","position":4,"is_corresponding":false},{"id":732904,"name":"Rajarajan A. Thandavarayan","orcid":"0000-0001-8452-2903","position":5,"is_corresponding":false},{"id":253434,"name":"Rahul Neupane","orcid":null,"position":0,"is_corresponding":true}],"reference_count":10,"raw_metadata":null,"created_at":"2026-07-19T00:30:01.051685Z","pmid":"36082691","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":[]}