{"doi":"10.3390/cells12101373","title":"Cardiovascular Protective Effects of NP-6A4, a Drug with the FDA Designation for Pediatric Cardiomyopathy, in Female Rats with Obesity and Pre-Diabetes","abstract":"BACKGROUND: Obese and pre-diabetic women have a higher risk for cardiovascular death than age-matched men with the same symptoms, and there are no effective treatments. We reported that obese and pre-diabetic female Zucker Diabetic Fatty (ZDF-F) rats recapitulate metabolic and cardiac pathology of young obese and pre-diabetic women and exhibit suppression of cardio-reparative AT2R. Here, we investigated whether NP-6A4, a new AT2R agonist with the FDA designation for pediatric cardiomyopathy, mitigate heart disease in ZDF-F rats by restoring AT2R expression. METHODS: ZDF-F rats on a high-fat diet (to induce hyperglycemia) were treated with saline, NP-6A4 (10 mg/kg/day), or NP-6A4 + PD123319 (AT2R-specific antagonist, 5 mg/kg/day) for 4 weeks (n = 21). Cardiac functions, structure, and signaling were assessed by echocardiography, histology, immunohistochemistry, immunoblotting, and cardiac proteome analysis. RESULTS: < 0.05). NP-6A4 activated a new 8-protein autophagy network and increased autophagy marker LC3-II but suppressed autophagy receptor p62 and autophagy inhibitor Rubicon. Co-treatment with AT2R antagonist PD123319 suppressed NP-6A4's protective effects, confirming that NP-6A4 acts through AT2R. NP-6A4-AT2R-induced cardioprotection was independent of changes in body weight, hyperglycemia, hyperinsulinemia, or blood pressure. CONCLUSIONS: Cardiac autophagy impairment underlies heart disease induced by obesity and pre-diabetes, and there are no drugs to re-activate autophagy. We propose that NP-6A4 can be an effective drug to reactivate cardiac autophagy and treat obesity- and pre-diabetes-induced heart disease, particularly for young and obese women.","journal":"Cells","year":2023,"id":352567,"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":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9456,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1098911,"name":"Asma Boukhalfa","orcid":null,"position":1,"is_corresponding":false},{"id":275598,"name":"Vincent G. DeMarco","orcid":"0000-0003-2092-9995","position":2,"is_corresponding":false},{"id":1098912,"name":"Alexander Mehm","orcid":null,"position":3,"is_corresponding":false},{"id":739678,"name":"Abuzar Mahmood","orcid":"0000-0002-2448-4818","position":4,"is_corresponding":false},{"id":1098421,"name":"Pei Liu","orcid":"0009-0006-0772-8434","position":5,"is_corresponding":false},{"id":1098913,"name":"Yinian Tang","orcid":null,"position":6,"is_corresponding":false},{"id":740384,"name":"Madhavi Gavini","orcid":null,"position":7,"is_corresponding":false},{"id":438360,"name":"Brian Mooney","orcid":"0000-0001-8096-3226","position":8,"is_corresponding":false},{"id":392222,"name":"Howard H. Chen","orcid":"0000-0002-5145-0584","position":9,"is_corresponding":false},{"id":329250,"name":"Lakshmi Pulakat","orcid":"0000-0002-1430-2945","position":10,"is_corresponding":false},{"id":658489,"name":"Anthony Belenchia","orcid":"0000-0001-6480-7290","position":0,"is_corresponding":true}],"reference_count":71,"raw_metadata":null,"created_at":"2026-07-19T01:12:54.209378Z","pmid":"37408206","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":[]}