Functional Inhibition of Valosin-Containing Protein Induces Cardiac Dilation and Dysfunction in a New Dominant-Negative Transgenic Mouse Model

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...

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Autores principales:	Xiaonan Sun, Ning Zhou, Ben Ma, Wenqian Wu, Shaunrick Stoll, Lo Lai, Gangjian Qin, Hongyu Qiu
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	valosin-containing protein dilated cardiomyopathy nuclear translocation co-factor interaction P47 nuclear protein localization protein 4 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/edd7597b2f3f4e32b0397aa06d10e564
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spelling	oai:doaj.org-article:edd7597b2f3f4e32b0397aa06d10e5642021-11-25T17:08:38ZFunctional Inhibition of Valosin-Containing Protein Induces Cardiac Dilation and Dysfunction in a New Dominant-Negative Transgenic Mouse Model10.3390/cells101128912073-4409https://doaj.org/article/edd7597b2f3f4e32b0397aa06d10e5642021-10-01T00:00:00Zhttps://www.mdpi.com/2073-4409/10/11/2891https://doaj.org/toc/2073-4409Valosin-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.Xiaonan SunNing ZhouBen MaWenqian WuShaunrick StollLo LaiGangjian QinHongyu QiuMDPI AGarticlevalosin-containing proteindilated cardiomyopathynuclear translocationco-factor interactionP47nuclear protein localization protein 4Biology (General)QH301-705.5ENCells, Vol 10, Iss 2891, p 2891 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	valosin-containing protein dilated cardiomyopathy nuclear translocation co-factor interaction P47 nuclear protein localization protein 4 Biology (General) QH301-705.5
spellingShingle	valosin-containing protein dilated cardiomyopathy nuclear translocation co-factor interaction P47 nuclear protein localization protein 4 Biology (General) QH301-705.5 Xiaonan Sun Ning Zhou Ben Ma Wenqian Wu Shaunrick Stoll Lo Lai Gangjian Qin Hongyu Qiu Functional Inhibition of Valosin-Containing Protein Induces Cardiac Dilation and Dysfunction in a New Dominant-Negative Transgenic Mouse Model
description	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.
format	article
author	Xiaonan Sun Ning Zhou Ben Ma Wenqian Wu Shaunrick Stoll Lo Lai Gangjian Qin Hongyu Qiu
author_facet	Xiaonan Sun Ning Zhou Ben Ma Wenqian Wu Shaunrick Stoll Lo Lai Gangjian Qin Hongyu Qiu
author_sort	Xiaonan Sun
title	Functional Inhibition of Valosin-Containing Protein Induces Cardiac Dilation and Dysfunction in a New Dominant-Negative Transgenic Mouse Model
title_short	Functional Inhibition of Valosin-Containing Protein Induces Cardiac Dilation and Dysfunction in a New Dominant-Negative Transgenic Mouse Model
title_full	Functional Inhibition of Valosin-Containing Protein Induces Cardiac Dilation and Dysfunction in a New Dominant-Negative Transgenic Mouse Model
title_fullStr	Functional Inhibition of Valosin-Containing Protein Induces Cardiac Dilation and Dysfunction in a New Dominant-Negative Transgenic Mouse Model
title_full_unstemmed	Functional Inhibition of Valosin-Containing Protein Induces Cardiac Dilation and Dysfunction in a New Dominant-Negative Transgenic Mouse Model
title_sort	functional inhibition of valosin-containing protein induces cardiac dilation and dysfunction in a new dominant-negative transgenic mouse model
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/edd7597b2f3f4e32b0397aa06d10e564
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Functional Inhibition of Valosin-Containing Protein Induces Cardiac Dilation and Dysfunction in a New Dominant-Negative Transgenic Mouse Model

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