Controlled and cardiac-restricted overexpression of the arginine vasopressin V1A receptor causes reversible left ventricular dysfunction through Gαq-mediated cell signaling.

dc.contributor.author

Li, Xue

dc.contributor.author

Chan, Tung O

dc.contributor.author

Myers, Valerie

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Chowdhury, Ibrul

dc.contributor.author

Zhang, Xue-Qian

dc.contributor.author

Song, Jianliang

dc.contributor.author

Zhang, Jin

dc.contributor.author

Andrel, Jocelyn

dc.contributor.author

Funakoshi, Hajime

dc.contributor.author

Robbins, Jeffrey

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Koch, Walter J

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Hyslop, Terry

dc.contributor.author

Cheung, Joseph Y

dc.contributor.author

Feldman, Arthur M

dc.date.accessioned

2024-11-14T23:26:25Z

dc.date.available

2024-11-14T23:26:25Z

dc.date.issued

2011-08

dc.description.abstract

Background

[Arg8]-vasopressin (AVP) activates 3 G-protein-coupled receptors: V1A, V2, and V1B. The AVP-V1A receptor is the primary AVP receptor in the heart; however, its role in cardiac homeostasis is controversial. To better understand AVP-mediated signaling in the heart, we created a transgenic mouse with controlled overexpression of the V1A receptor.

Methods and results

The V1A receptor transgene was placed under the control of the tetracycline-regulated, cardiac-specific α-myosin heavy chain promoter (V1A-TG). V1A-TG mice had a normal cardiac function phenotype at 10 weeks of age; however, by 24 weeks of age, tetracycline-transactivating factor/V1A-TG mouse hearts had reduced cardiac function, cardiac hypertrophy, and dilatation of the ventricular cavity. Contractile dysfunction was also observed in isolated adult cardiac myocytes. When V1A receptor transgene was induced to be expressed in adult mice (V1A-TG(Ind)), left ventricular dysfunction and dilatation were also seen, albeit at a later time point. Because the V1A receptor mediates cell signaling through Gα(q) protein, we blocked Gα(q) signaling by crossing tetracycline-transactivating factor/V1A mice with transgenic mice that expressed a small inhibitory peptide against Gα(q). Gα(q) blockade abrogated the development of the heart failure phenotype in tetracycline-transactivating factor/V1A-TG mice. The heart failure phenotype could be reversed by administration of doxycycline.

Conclusions

Our results demonstrate a role for V1A-mediated signaling in the development of heart failure and support a role for V1A blockade in the treatment of patients with elevated levels of vasopressin.
dc.identifier

CIRCULATIONAHA.111.021352

dc.identifier.issn

0009-7322

dc.identifier.issn

1524-4539

dc.identifier.uri

https://hdl.handle.net/10161/31651

dc.language

eng

dc.publisher

Ovid Technologies (Wolters Kluwer Health)

dc.relation.ispartof

Circulation

dc.relation.isversionof

10.1161/circulationaha.111.021352

dc.rights.uri

https://creativecommons.org/licenses/by-nc/4.0

dc.subject

Myocardium

dc.subject

Animals

dc.subject

Mice, Inbred C57BL

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Mice, Transgenic

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Humans

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Mice

dc.subject

Prenatal Exposure Delayed Effects

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Cardiomyopathies

dc.subject

Ventricular Dysfunction, Left

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Calcium

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Insulin

dc.subject

GTP-Binding Protein alpha Subunits, Gq-G11

dc.subject

Extracellular Signal-Regulated MAP Kinases

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Receptors, Vasopressin

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MAP Kinase Signaling System

dc.subject

Gene Expression

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Action Potentials

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Pregnancy

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Myocardial Contraction

dc.subject

Phenotype

dc.subject

Female

dc.subject

Male

dc.subject

Inositol 1,4,5-Trisphosphate Receptors

dc.subject

Heart Failure

dc.title

Controlled and cardiac-restricted overexpression of the arginine vasopressin V1A receptor causes reversible left ventricular dysfunction through Gαq-mediated cell signaling.

dc.type

Journal article

duke.contributor.orcid

Koch, Walter J|0000-0002-8522-530X

pubs.begin-page

572

pubs.end-page

581

pubs.issue

5

pubs.organisational-group

Duke

pubs.organisational-group

School of Medicine

pubs.organisational-group

Basic Science Departments

pubs.organisational-group

Clinical Science Departments

pubs.organisational-group

Biostatistics & Bioinformatics

pubs.organisational-group

Surgery

pubs.organisational-group

Surgery, Cardiovascular and Thoracic Surgery

pubs.organisational-group

Biostatistics & Bioinformatics, Division of Translational Biomedical

pubs.publication-status

Published

pubs.volume

124

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