{"doi":"10.3390/ijms26199383","title":"TRPC6 Deficiency Attenuates Mitochondrial and Cardiac Dysfunction in Heart Failure with Preserved Ejection Fraction Induced by High-Fat Diet Plus L-NAME","abstract":"influx, is expressed in the heart and implicated in pathological cardiac hypertrophy. However, the role of TRPC6 in regulating cardiac mitochondrial metabolism and contributing to development of HFpEF remains unclear. We examined whether TRPC6 deficiency prevents mitochondrial dysfunction and offers cardiac protection in a mouse model of HFpEF induced by high-fat diet (HFD) for 12 weeks combined with L-NAME administration during the final 8 weeks in TRPC6 knockout (KO) and wild-type (WT) control mice. Cardiac systolic and diastolic functions were assessed at baseline, 4 and 8 weeks after HFD+L-NAME. Dobutamine-induced stress test and treadmill exercise test were performed at the end of the protocol to evaluate cardiac reserve capacity and exercise tolerance. Mitochondrial oxygen consumption rate (OCR) and mitochondrial-derived reactive oxygen species (ROS) generation were examined in isolated cardiac fibers. WT mice subjected to HFD+L-NAME developed cardiac hypertrophy, diastolic dysfunction, and exercise intolerance, whereas TRPC6 KO mice, under the same conditions, maintained preserved diastolic function, exercise tolerance, and cardiac reserve. We also observed increased TRPC6 in mitochondria, as well as caspase-9 activation and impaired mitochondrial respiration in WT mice. In contrast, TRPC6 KO mice exhibited preserved mitochondrial OCR and attenuated mitochondrial ROS generation. In summary, TRPC6 deficiency prevents the development of HFpEF by mitigating diastolic dysfunction, preserving cardiac reserve capacity, and attenuating mitochondrial dysfunction.","journal":"International Journal of Molecular Sciences","year":2025,"id":547184,"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":0.9511,"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":968209,"name":"Yiling Fu","orcid":null,"position":1,"is_corresponding":false},{"id":1440040,"name":"Xuemei Dai","orcid":null,"position":2,"is_corresponding":false},{"id":239704,"name":"Jussara M. do Carmo","orcid":"0000-0003-0471-0512","position":3,"is_corresponding":false},{"id":239700,"name":"Alexandre A. da Silva","orcid":"0000-0003-4504-0607","position":4,"is_corresponding":false},{"id":239699,"name":"Alan J. Mouton","orcid":"0000-0001-5973-3071","position":5,"is_corresponding":false},{"id":239701,"name":"Ana Carolina Mieko Omoto","orcid":"0000-0003-1062-7109","position":6,"is_corresponding":false},{"id":1244910,"name":"Robert W. Spitz","orcid":"0009-0007-4270-6932","position":7,"is_corresponding":false},{"id":1002871,"name":"Lucas Wang","orcid":"0000-0002-0597-1266","position":8,"is_corresponding":false},{"id":239698,"name":"John E. Hall","orcid":"0000-0001-9867-5855","position":9,"is_corresponding":false},{"id":1439635,"name":"Zhen Wang","orcid":"0000-0002-8028-8942","position":10,"is_corresponding":false},{"id":239703,"name":"Xuan Li","orcid":"0000-0001-5781-1662","position":0,"is_corresponding":true}],"reference_count":46,"raw_metadata":null,"created_at":"2026-07-19T02:53:41.314800Z","pmid":"41096654","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":[]}