Loss of dynamic regulation of G protein-coupled receptor kinase 2 by nitric oxide leads to cardiovascular dysfunction with aging.

dc.contributor.author

Lieu, Melissa

dc.contributor.author

Traynham, Christopher J

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de Lucia, Claudio

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Pfleger, Jessica

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Piedepalumbo, Michela

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Roy, Rajika

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Petovic, Jennifer

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Landesberg, Gavin

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Forrester, Steven J

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Hoffman, Matthew

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Grisanti, Laurel A

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Yuan, Ancai

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Gao, Erhe

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Drosatos, Konstantinos

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Eguchi, Satoru

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Scalia, Rosario

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Tilley, Douglas G

dc.contributor.author

Koch, Walter J

dc.date.accessioned

2023-09-01T16:46:13Z

dc.date.available

2023-09-01T16:46:13Z

dc.date.issued

2020-05

dc.date.updated

2023-09-01T16:46:12Z

dc.description.abstract

Nitric oxide (NO) and S-nitrosothiol (SNO) are considered cardio- and vasoprotective substances. We now understand that one mechanism in which NO/SNOs provide cardiovascular protection is through their direct inhibition of cardiac G protein-coupled receptor (GPCR) kinase 2 (GRK2) activity via S-nitrosylation of GRK2 at cysteine 340 (C340). This maintains GPCR homeostasis, including β-adrenergic receptors, through curbing receptor GRK2-mediated desensitization. Previously, we have developed a knockin mouse (GRK2-C340S) where endogenous GRK2 is resistant to dynamic S-nitrosylation, which led to increased GRK2 desensitizing activity. This unchecked regulation of cardiac GRK2 activity resulted in significantly more myocardial damage after ischemic injury that was resistant to NO-mediated cardioprotection. Although young adult GRK2-C340S mice show no overt phenotype, we now report that as these mice age, they develop significant cardiovascular dysfunction due to the loss of SNO-mediated GRK2 regulation. This pathological phenotype is apparent as early as 12 mo of age and includes reduced cardiac function, increased cardiac perivascular fibrosis, and maladaptive cardiac hypertrophy, which are common maladies found in patients with cardiovascular disease (CVD). There are also vascular reactivity and aortic abnormalities present in these mice. Therefore, our data demonstrate that a chronic and global increase in GRK2 activity is sufficient to cause cardiovascular remodeling and dysfunction, likely due to GRK2's desensitizing effects in several tissues. Because GRK2 levels have been reported to be elevated in elderly CVD patients, GRK2-C340 mice can give insight into the aged-molecular landscape leading to CVD.NEW & NOTEWORTHY Research on G protein-coupled receptor kinase 2 (GRK2) in the setting of cardiovascular aging is largely unknown despite its strong established functions in cardiovascular physiology and pathophysiology. This study uses a mouse model of chronic GRK2 overactivity to further investigate the consequences of long-term GRK2 on cardiac function and structure. We report for the first time that chronic GRK2 overactivity was able to cause cardiac dysfunction and remodeling independent of surgical intervention, highlighting the importance of GRK activity in aged-related heart disease.

dc.identifier.issn

0363-6135

dc.identifier.issn

1522-1539

dc.identifier.uri

https://hdl.handle.net/10161/28938

dc.language

eng

dc.publisher

American Physiological Society

dc.relation.ispartof

American journal of physiology. Heart and circulatory physiology

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10.1152/ajpheart.00094.2020

dc.subject

Myocardium

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Heart

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Animals

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Mice

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Heart Diseases

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Nitric Oxide

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Aging

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Homeostasis

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Mutation

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Female

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Male

dc.subject

G Protein-Coupled Inwardly-Rectifying Potassium Channels

dc.title

Loss of dynamic regulation of G protein-coupled receptor kinase 2 by nitric oxide leads to cardiovascular dysfunction with aging.

dc.type

Journal article

pubs.begin-page

H1162

pubs.end-page

H1175

pubs.issue

5

pubs.organisational-group

Duke

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School of Medicine

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Clinical Science Departments

pubs.organisational-group

Surgery

pubs.organisational-group

Surgery, Cardiovascular and Thoracic Surgery

pubs.publication-status

Published

pubs.volume

318

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