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Updated: Oct 12, 2025
Transverse Aortic Constriction in Mice
Published on: April 21, 2010
Functional Inhibition of Valosin-Containing Protein Induces Cardiac Dilation and Dysfunction in a New
Xiaonan Sun1, Ning Zhou2, Ben Ma1
1Center for Molecular and Translational Medicine, Institute of Biomedical Science, Georgia State University, Atlanta, GA 30303, USA.
Abstract:
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.
Insights
Impaired valosin-containing protein (VCP) function in the heart leads to cardiac dilation and dysfunction. This study developed a novel mouse model to investigate VCP
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Protein Biochemistry
Background:
- Valosin-containing protein (VCP) is crucial for cellular homeostasis and implicated in cardiac stress responses.
- VCP mutations are linked to human dilated cardiomyopathy, but its physiological role in the heart is unclear.
- VCP knockout mice exhibit embryonic lethality, necessitating alternative models to study cardiac VCP function.
Purpose of the Study:
- To investigate the essential role of VCP in the heart under physiological conditions.
- To elucidate the mechanisms by which impaired VCP activity affects cardiac function.
- To establish a cardiac-specific dominant-negative VCP transgenic (DN-VCP TG) mouse model.
Main Methods:
- Generation of cardiac-specific dominant-negative VCP transgenic (DN-VCP TG) mice.
- Echocardiography to assess cardiac structure and function over time.
- Biochemical assays to measure cardiac ATPase activity and protein-cofactor interactions.
Main Results:
- Cardiac-specific overexpression of DN-VCP resulted in progressive cardiac dilation and impaired cardiac function in aging mice.
- DN-VCP inhibited VCP's ATPase activity without altering endogenous VCP expression.
- Impaired VCP function disrupted cytoplasmic/nuclear shuttling and altered cofactor binding, favoring inhibitory interactions.
Conclusions:
- Impaired VCP activity in the heart leads to cardiac dysfunction and dilation, mimicking aspects of cardiomyopathy.
- The DN-VCP TG mouse is a valuable model for studying VCP's role in cardiac physiology and pathology.
- Understanding VCP cofactor interactions is critical for deciphering its cardiac function and developing therapeutic strategies.
