{"doi":"10.1101/2025.07.03.662389","title":"Cardiomyocyte-specific expression of HIF-1α mediates the cardioprotective effects of Growth Hormone Releasing Hormone (GHRH)","abstract":"Abstract Heart failure (HF) with preserved ejection fraction (HFpEF) carries a high mortality and remains a major therapeutic challenge. Effective, targeted therapies capable of reversing HFpEF pathophysiology are urgently needed. We previously demonstrated that activation of the cardiac growth hormone-releasing hormone (GHRH) pathway using high potency synthetic agonists of GHRH (GHRH-agonists: MR-356 and MR-409) improves the HFpEF phenotype in both large and small animal models, including in a murine model of cardiometabolic HFpEF (High fat diet + the nitric oxide synthase inhibitor L-NAME [HFD+L-NAME]). Here we sought to define the downstream signaling pathways responsible for this effect. A transcriptomic screen in human iPSC-derived cardiomyocytes (hiPSC-CMs) identified the hypoxia-inducible factor (HIF)-1α pathway as being activated by GHRH receptor (GHRHR) signaling, revealing an oxygen-independent mechanism of HIF-1α activation. Based on this finding, we investigated the interaction between the cardioprotective effects of the GHRH-agonist MR-356 and HIF-1α pathway activation in the murine HFD+L-NAME model of cardiometabolic HFpEF. We generated a cardiomyocyte-specific HIF-1α knockout (HIF-1α CM KO) mouse line and demonstrated that our previously reported beneficial effects of GHRH-agonist administration were completely abolished in HIF-1α CM KO mice. Together, these findings establish the GHRHR-HIF-1α axis as a central pathway integrating metabolic and contractile remodeling, suggesting that therapeutic targeting of this axis represents a novel disease-modifying approach to treating cardiometabolic HFpEF.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":558436,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9623,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":569761,"name":"Lauro M Takeuchi","orcid":"0000-0002-4517-9548","position":1,"is_corresponding":false},{"id":408638,"name":"Wayne Balkan","orcid":"0000-0003-0405-0489","position":2,"is_corresponding":false},{"id":401870,"name":"Amarylis Wanschel","orcid":"0000-0002-5603-7983","position":3,"is_corresponding":false},{"id":1384765,"name":"Konstantinos Chatzistergos","orcid":"0000-0003-2755-644X","position":4,"is_corresponding":false},{"id":397419,"name":"Shathiyah Kulandavelu","orcid":"0000-0003-0966-7613","position":5,"is_corresponding":false},{"id":422269,"name":"Russell Saltzman","orcid":"0000-0003-0494-3869","position":6,"is_corresponding":false},{"id":397422,"name":"Lina A. Shehadeh","orcid":"0000-0003-2095-9326","position":7,"is_corresponding":false},{"id":993381,"name":"Wei Sha","orcid":"0000-0003-4740-2325","position":8,"is_corresponding":false},{"id":569763,"name":"Andrew V. Schally","orcid":"0000-0003-1273-6747","position":9,"is_corresponding":false},{"id":227349,"name":"Stefan Kurtenbach","orcid":"0000-0002-7445-596X","position":10,"is_corresponding":false},{"id":88819,"name":"Joshua M. Hare","orcid":"0000-0002-7751-5032","position":11,"is_corresponding":false},{"id":569760,"name":"Rosemeire M. Kanashiro‐Takeuchi","orcid":"0000-0002-7305-9172","position":0,"is_corresponding":true}],"reference_count":57,"raw_metadata":null,"created_at":"2026-07-19T02:55:25.969263Z","pmid":"40672240","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":[]}