{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T14:12:00Z","timestamp":1791987120952,"version":"4.4.0"},"reference-count":48,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2025,9,25]],"date-time":"2025-09-25T00:00:00Z","timestamp":1758758400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"crossref","award":["R00DK113280"],"award-info":[{"award-number":["R00DK113280"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"crossref","award":["R01 DK121411"],"award-info":[{"award-number":["R01 DK121411"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"crossref","award":["1R01HL163076"],"award-info":[{"award-number":["1R01HL163076"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"crossref","award":["R01HL166737"],"award-info":[{"award-number":["R01HL166737"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"crossref","award":["P20GM104357"],"award-info":[{"award-number":["P20GM104357"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"crossref","award":["P30GM149404"],"award-info":[{"award-number":["P30GM149404"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"crossref","award":["U54 GM115428"],"award-info":[{"award-number":["U54 GM115428"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000968","name":"the American Heart Association","doi-asserted-by":"publisher","award":["908950"],"award-info":[{"award-number":["908950"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["IJMS"],"abstract":"<jats:p>Transient receptor potential canonical channel type 6 (TRPC6), a non-selective cation channel that mediates Ca2+ 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.<\/jats:p>","DOI":"10.3390\/ijms26199383","type":"journal-article","created":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T06:02:52Z","timestamp":1758866572000},"page":"9383","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["TRPC6 Deficiency Attenuates Mitochondrial and Cardiac Dysfunction in Heart Failure with Preserved Ejection Fraction Induced by High-Fat Diet Plus L-NAME"],"prefix":"10.3390","volume":"26","author":[{"given":"Xuan","family":"Li","sequence":"first","affiliation":[{"name":"Department of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiorenal and Metabolic Diseases Research Center, University of Mississippi Medical Center, Jackson, MS 39216, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiling","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiorenal and Metabolic Diseases Research Center, University of Mississippi Medical Center, Jackson, MS 39216, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuemei","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiorenal and Metabolic Diseases Research Center, University of Mississippi Medical Center, Jackson, MS 39216, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jussara M.","family":"do Carmo","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiorenal and Metabolic Diseases Research Center, University of Mississippi Medical Center, Jackson, MS 39216, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandre A.","family":"da Silva","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiorenal and Metabolic Diseases Research Center, University of Mississippi Medical Center, Jackson, MS 39216, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan J.","family":"Mouton","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiorenal and Metabolic Diseases Research Center, University of Mississippi Medical Center, Jackson, MS 39216, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1062-7109","authenticated-orcid":false,"given":"Ana C. M.","family":"Omoto","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiorenal and Metabolic Diseases Research Center, University of Mississippi Medical Center, Jackson, MS 39216, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-4270-6932","authenticated-orcid":false,"given":"Robert W.","family":"Spitz","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiorenal and Metabolic Diseases Research Center, University of Mississippi Medical Center, Jackson, MS 39216, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucas","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiorenal and Metabolic Diseases Research Center, University of Mississippi Medical Center, Jackson, MS 39216, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John E.","family":"Hall","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiorenal and Metabolic Diseases Research Center, University of Mississippi Medical Center, Jackson, MS 39216, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8028-8942","authenticated-orcid":false,"given":"Zhen","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiorenal and Metabolic Diseases Research Center, University of Mississippi Medical Center, Jackson, MS 39216, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1001\/jama.2023.2020","article-title":"Heart Failure with Preserved Ejection Fraction: A Review","volume":"329","author":"Redfield","year":"2023","journal-title":"JAMA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"101027","DOI":"10.1016\/j.jacadv.2024.101027","article-title":"Long-Term Outcomes of Heart Failure with Preserved or Mid-Range Ejection Fraction in the United States","volume":"3","author":"Sun","year":"2024","journal-title":"JACC Adv."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1016\/j.jchf.2023.05.010","article-title":"Design and Baseline Characteristics of STEP-HFpEF Program Evaluating Semaglutide in Patients with Obesity HFpEF Phenotype","volume":"11","author":"Kosiborod","year":"2023","journal-title":"JACC Heart Fail."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1906","DOI":"10.1161\/CIRCRESAHA.122.320257","article-title":"Heart Failure with Preserved Ejection Fraction: Heterogeneous Syndrome, Diverse Preclinical Models","volume":"130","author":"Roh","year":"2022","journal-title":"Circ. 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