{"doi":"10.7150/thno.48297","title":"Reprogramming of miR-181a/DNA methylation patterns contribute to the maternal nicotine exposure-induced fetal programming of cardiac ischemia-sensitive phenotype in postnatal life","abstract":"Background: E-cigarette and other novel electronic nicotine delivery systems (ENDS) have recently entered the market at a rapid pace. The community desperately needs answers about the health effects of ENDS. The present study tested the hypothesis that perinatal nicotine exposure (PNE) causes a gender-dependent increase in vulnerability of the heart to ischemia-reperfusion (I/R) injury and cardiac dysfunction in male rat offspring via reprogramming of the miRNA-181a (miR-181a)-mediated signaling pathway and that miR-181a antisense could rescue this phenotype. Methods: Nicotine or saline was administered to pregnant rats via subcutaneous osmotic minipumps from gestational day 4 until postnatal day 10. Cardiac function and molecular biological experiments were conducted in ~3-month-old offspring. Results: PNE enhanced I/R-induced cardiac dysfunction and infarction in adult male but not in female offspring, which was associated with miR-181a over-expression in left ventricle tissues. In addition, PNE enhanced offspring cardiac angiotensin receptor (ATR) expressions via specific CpG hypomethylation of AT1R/AT2R promoter. Furthermore, PNE attenuated cardiac lncRNA H19 levels, but up-regulated cardiac TGF-/Smads family proteins and consequently up-regulated autophagy-related protein (Atg-5, beclin-1, LC3 II, p62) expression in the male offspring. Of importance, treatment with miR-181a antisense eliminated the PNE's effect on miR-181a expression/H19 levels and reversed PNE-mediated I/R-induced cardiac infarction and dysfunction in male offspring. Furthermore, miR-181a antisense also attenuated the effect of PNE on AT1R/AT2R/TGF-/Smads/autophagy-related biomarkers in the male offspring. Conclusion: Our data suggest that PNE could induce a reprogramming of cardiac miR-181a expression/DNA methylation pattern, which epigenetically modulates ATR/TGF-/autophagy signaling pathways, leading to gender-dependent development of ischemia-sensitive phenotype in postnatal life. Furthermore, miR-181a could severe as a potential therapeutic target for rescuing this phenotype.","journal":"Theranostics","year":2020,"id":103488,"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":25,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9559,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":280723,"name":"Peng Zhang","orcid":"0000-0002-6218-1885","position":1,"is_corresponding":false},{"id":323029,"name":"Yong Li","orcid":"0000-0002-8910-9787","position":2,"is_corresponding":false},{"id":361590,"name":"Bailin Liu","orcid":"0000-0002-6736-5333","position":3,"is_corresponding":false},{"id":504311,"name":"Yanyan Zhang","orcid":"0000-0001-7801-0215","position":4,"is_corresponding":false},{"id":291057,"name":"Li Zhang","orcid":"0000-0002-9386-8938","position":5,"is_corresponding":false},{"id":361591,"name":"Xuesi M. Shao","orcid":"0000-0002-5165-347X","position":6,"is_corresponding":false},{"id":504312,"name":"Jian Zhuang","orcid":"0000-0002-2357-4934","position":7,"is_corresponding":false},{"id":361592,"name":"Daliao Xiao","orcid":"0000-0003-0147-2758","position":8,"is_corresponding":false},{"id":504310,"name":"Jie Jian","orcid":"0000-0001-5841-6189","position":0,"is_corresponding":true}],"reference_count":54,"raw_metadata":null,"created_at":"2026-07-18T22:42:48.999009Z","pmid":"33052248","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":[]}