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Beta-3 adrenergic receptor overexpression reverses aortic stenosis-induced heart failure and restores balanced mitochondrial dynamics

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Beta-3 adrenergic receptor overexpression reverses aortic stenosis-induced heart failure and restores balanced mitochondrial dynamics

dc.contributor.author	Pun García, Andrés
dc.contributor.author	Clemente Moragón, Agustín
dc.contributor.author	Villena Gutierrez, Rocio
dc.contributor.author	Gómez, Mónica
dc.contributor.author	Sanz Rosa, David
dc.contributor.author	Díaz Guerra, Anabel
dc.contributor.author	Prados, Belén
dc.contributor.author	Medina, Juan Pablo
dc.contributor.author	Montó Guillot, Fermí Josep
dc.contributor.author	Ivorra Insa, María Dolores
dc.contributor.author	Márquez-López, Cristina
dc.contributor.author	Cannavo, Alessandro
dc.contributor.author	Bernal, Juan A.
dc.contributor.author	Koch, Walter J.
dc.contributor.author	Fuster, Valentin
dc.contributor.author	De la Pompa, Jose Luis
dc.contributor.author	Oliver Pérez, Eduardo
dc.contributor.author	Ibanez, Borja
dc.date.accessioned	2023-04-28T10:49:53Z
dc.date.available	2023-04-28T10:49:53Z
dc.date.issued	2022
dc.identifier.citation	Pun García, Andrés Clemente Moragón, Agustín Villena Gutierrez, Rocio Gómez, Mónica Sanz Rosa, David Díaz Guerra, Anabel Prados, Belén Medina, Juan Pablo Montó Guillot, Fermí Josep Ivorra Insa, María Dolores Márquez-López, Cristina Cannavo, Alessandro Bernal, Juan A. Koch, Walter J. Fuster, Valentin De la Pompa, Jose Luis Oliver Pérez, Eduardo Ibanez, Borja 2022 Beta-3 adrenergic receptor overexpression reverses aortic stenosis-induced heart failure and restores balanced mitochondrial dynamics Basic Research in Cardiology 117 1 62
dc.identifier.uri	https://hdl.handle.net/10550/86244
dc.description.abstract	Aortic stenosis (AS) is associated with left ventricular (LV) hypertrophy and heart failure (HF). There is a lack of therapies able to prevent/revert AS-induced HF. Beta3 adrenergic receptor (β3AR) signaling is beneficial in several forms of HF. Here, we studied the potential beneficial effect of β3AR overexpression on AS-induced HF. Selective β3AR stimulation had a positive inotropic effect. Transgenic mice constitutively overexpressing human β3AR in the heart (c-hβ3tg) were protected from the development of HF in response to induced AS, and against cardiomyocyte mitochondrial dysfunction (fragmented mitochondria with remodeled cristae and metabolic reprogramming featuring altered substrate use). Similar beneficial effects were observed in wild-type mice inoculated with adeno-associated virus (AAV9) inducing cardiac-specific overexpression of human β3AR before AS induction. Moreover, AAV9-hβ3AR injection into wild-type mice at late disease stages, when cardiac hypertrophy and metabolic reprogramming are already advanced, reversed the HF phenotype and restored balanced mitochondrial dynamics, demonstrating the potential of gene-therapy-mediated β3AR overexpression in AS. Mice with cardiac specific ablation of Yme1l (cYKO), characterized by fragmented mitochondria, showed an increased mortality upon AS challenge. AAV9-hβ3AR injection in these mice before AS induction reverted the fragmented mitochondria phenotype and rescued them from death. In conclusion, our results step out that β3AR overexpression might have translational potential as a therapeutic strategy in AS-induced HF.
dc.language.iso	eng
dc.relation.ispartof	Basic Research in Cardiology, 2022, vol. 117, num. 1, p. 62
dc.subject	Medicina
dc.subject	Medicina Investigació
dc.title	Beta-3 adrenergic receptor overexpression reverses aortic stenosis-induced heart failure and restores balanced mitochondrial dynamics
dc.type	journal article
dc.date.updated	2023-04-28T10:49:54Z
dc.identifier.doi	10.1007/s00395-022-00966-z
dc.identifier.idgrec	157688
dc.rights.accessRights	open access