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

• DOI: 10.1007/s00395-022-00966-z
• Publication Date: 2022-11-29T07:30:29Z
• Authors: Andrés Pun-García; Agustín Clemente-...; Rocio Villena-Gut...; Monica Gómez; David Sanz-Rosa; Anabel Díaz-Guerra; Belén Prados; Juan Pablo Medina; Fermí Montó; Maria Dolores Ivorra; Cristina Márquez-...; Alessandro Cannavo; Juan A. Bernal; Walter J. Koch; Valentin Fuster; José Luis de la P...; Eduardo Oliver; Borja Ibanez
• Keywords: Pressure overload

Abstract Aortic stenosis (AS) is associated with left ventricular (LV) hypertrophy and heart failure (HF). There a lack of therapies able to prevent/revert AS-induced HF. Beta3 adrenergic receptor (β3AR) signaling beneficial in several forms Here, we studied the potential effect β3AR overexpression on Selective stimulation had positive inotropic effect. Transgenic mice constitutively overexpressing human (c-hβ3tg) were protected from development HF response induced AS, against cardiomyocyte mitochondrial dysfunction (fragmented mitochondria remodeled cristae metabolic reprogramming featuring altered substrate use). Similar effects observed wild-type inoculated adeno-associated virus (AAV9) inducing cardiac-specific before AS induction. Moreover, AAV9-hβ3AR injection into at late disease stages, when cardiac are already advanced, reversed phenotype restored balanced dynamics, demonstrating gene-therapy-mediated AS. Mice specific ablation Yme1l (cYKO), characterized by fragmented mitochondria, showed an increased mortality upon challenge. these induction reverted rescued them death. In conclusion, our results step out that might have translational as therapeutic strategy AS–induced