de Lucia, Claudio (2018) β-arrestin 2 deletion improves cardiac function during aging. [Tesi di dottorato]


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Item Type: Tesi di dottorato
Resource language: English
Title: β-arrestin 2 deletion improves cardiac function during aging
de Lucia,
Date: 2018
Number of Pages: 23
Institution: Università degli Studi di Napoli Federico II
Department: dep22
Dottorato: phd053
Ciclo di dottorato: 30
Coordinatore del Corso di dottorato:
Ferrara, NicolaUNSPECIFIED
Date: 2018
Number of Pages: 23
Keywords: Cardiac aging, arrestins, adrenergic receptors, ageing, sympathetic nervous system.
Settori scientifico-disciplinari del MIUR: Area 06 - Scienze mediche > MED/09 - Medicina interna
Area 06 - Scienze mediche > MED/11 - Malattie dell'apparato cardiovascolare
Date Deposited: 21 Dec 2017 09:12
Last Modified: 12 Apr 2019 09:05

Collection description

BACKGROUND: The pathophysiological changes of the aging human heart include left ventricular (LV) hypertrophy, diastolic dysfunction, increased cardiac fibrosis and reduced inotropic reserve. These changes make aged myocardium more susceptible to stress, leading to a high prevalence of cardiovascular diseases in the elderly population. The application of genetically modified aged mice has provided direct evidence of several critical molecular mechanisms involved in cardiac aging, such as altered adrenergic signaling. Importantly, both animal and human studies have shown an age-related β-adrenergic receptor (β-AR) dysfunction but the main mechanism involved is still unknown. Physiologically, when β-ARs are stimulated by agonists, the G protein-coupled receptor kinase 2 (GRK2) phosphorylates β-ARs that then become targets for binding of β-arrestins. This β-arrestin binding prevents their further coupling to the G protein, reducing the level of functional receptors and inducing their internalization. OBJECTIVE: In the present study we have tested the effects of β-arrestin-2 deletion on cardiac function and signaling in a murine model of aging. METHODS AND RESULTS: Genetically engineered, β-arrestin 2 KO and corresponding wild type (WT) male mice were enrolled to study physiological aging. We found that β-arrestin-2 deletion in aged mice is able to: a)improve LV contractility and dilatation b)enhance average and regional cardiac radial strain as well as radial SR during c)restore age-related cardiac β-AR desensitization d)reduce cardiac oxidative stress. CONCLUSIONS: Our study shows that β-arrestin 2 has a detrimental effect on the aged heart. β-arrestin 2 deletion reverses cardiac dysfunction and LV dilatation during aging. As a contributing mechanism, improved LV function is associated with restored β-AR density and reduced oxidative stress in aged hearts. Further, our results suggest β-arrestin 2 as a potential therapeutic target to limit age-related cardiac dysfunction.


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