{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T09:27:56Z","timestamp":1789464476611,"version":"build-2803163510"},"reference-count":47,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,10,26]],"date-time":"2021-10-26T00:00:00Z","timestamp":1635206400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HL115195-01, HL137962 , and HL142291."],"award-info":[{"award-number":["HL115195-01, HL137962 , and HL142291."]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Valosin-containing protein (VCP) was found to play a vital protective role against cardiac stresses. Genetic mutations of VCP are associated with human dilated cardiomyopathy. However, the essential role of VCP in the heart during the physiological condition remains unknown since the VCP knockout in mice is embryonically lethal. We generated a cardiac-specific dominant-negative VCP transgenic (DN-VCP TG) mouse to determine the effects of impaired VCP activity on the heart. Using echocardiography, we showed that cardiac-specific overexpression of DN-VCP induced a remarkable cardiac dilation and progressively declined cardiac function during the aging transition. Mechanistically, DN-VCP did not affect the endogenous VCP (EN-VCP) expression but significantly reduced cardiac ATPase activity in the DN-VCP TG mouse hearts, indicating a functional inhibition. DN-VCP significantly impaired the aging-related cytoplasmic\/nuclear shuffling of EN-VCP and its co-factors in the heart tissues and interrupted the balance of the VCP-cofactors interaction between the activating co-factors, ubiquitin fusion degradation protein 1 (UFD-1)\/nuclear protein localization protein 4 (NPL-4) complex, and its inhibiting co-factor P47, leading to the binding preference with the inhibitory co-factor, resulting in functional repression of VCP. This DN-VCP TG mouse provides a unique functional-inactivation model for investigating VCP in the heart in physiological and pathological conditions.<\/jats:p>","DOI":"10.3390\/cells10112891","type":"journal-article","created":{"date-parts":[[2021,10,26]],"date-time":"2021-10-26T23:49:52Z","timestamp":1635292192000},"page":"2891","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Functional Inhibition of Valosin-Containing Protein Induces Cardiac Dilation and Dysfunction in a New Dominant-Negative Transgenic Mouse Model"],"prefix":"10.3390","volume":"10","author":[{"given":"Xiaonan","family":"Sun","sequence":"first","affiliation":[{"name":"Center for Molecular and Translational Medicine, Institute of Biomedical Science, Georgia State University, Atlanta, GA 30303, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Zhou","sequence":"additional","affiliation":[{"name":"Division of Physiology, Department of Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA 92318, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ben","family":"Ma","sequence":"additional","affiliation":[{"name":"Center for Molecular and Translational Medicine, Institute of Biomedical Science, Georgia State University, Atlanta, GA 30303, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0452-9273","authenticated-orcid":false,"given":"Wenqian","family":"Wu","sequence":"additional","affiliation":[{"name":"Center for Molecular and Translational Medicine, Institute of Biomedical Science, Georgia State University, Atlanta, GA 30303, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaunrick","family":"Stoll","sequence":"additional","affiliation":[{"name":"Division of Physiology, Department of Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA 92318, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lo","family":"Lai","sequence":"additional","affiliation":[{"name":"Center for Molecular and Translational Medicine, Institute of Biomedical Science, Georgia State University, Atlanta, GA 30303, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gangjian","family":"Qin","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, School of Medicine and School of Engineering, University of Alabama at Birmingham, Birmingham, AL 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2436-8921","authenticated-orcid":false,"given":"Hongyu","family":"Qiu","sequence":"additional","affiliation":[{"name":"Center for Molecular and Translational Medicine, Institute of Biomedical Science, Georgia State University, Atlanta, GA 30303, USA"},{"name":"Division of Physiology, Department of Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA 92318, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1007\/s11010-016-2746-6","article-title":"Valosin-containing protein (VCP) promotes the growth, invasion, and metastasis of colorectal cancer through activation of STAT3 signaling","volume":"418","author":"Fu","year":"2016","journal-title":"Mol. 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