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

Andrés Pun-García, Agustín Clemente-Moragón, Rocio Villena-Gutierrez, Monica Gómez, David Sanz-Rosa, Anabel Díaz-Guerra, Belén Prados, Juan Pablo Medina, Fermí Montó, Maria Dolores Ivorra, Cristina Márquez-López, Alessandro Cannavo, Juan A. Bernal, Walter J. Koch, Valentin Fuster, José Luis de la Pompa, Eduardo Oliver, Borja Ibanez

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

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.

Original languageEnglish
Article number62
JournalBasic Research in Cardiology
Volume117
Issue number1
DOIs
StatePublished - Dec 2022

Keywords

  • Aortic stenosis
  • Beta adrenergic system
  • Heart failure
  • Hypertrophy
  • Metabolism
  • Mitochondria

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