Myocardial phosphoproteomics unveils a key role of DYRK1A in aortic valve replacement-induced reverse remodelling.

Abstract

Aortic valve stenosis (AVS) is a growing healthcare burden. Aortic valve replacement (AVR) remains the only effective treatment to eliminate pressure overload and triggers myocardial reverse remodelling (RR), with regression of hypertrophy, fibrosis and diastolic function normalisation. However, many patients show an incomplete RR, being at higher risk of death. We aimed to uncover pathways and new therapeutic targets for incomplete RR through myocardial (phospho)proteomics. AVS patients were categorised based on left ventricle mass regression (LVM): complete RR (≥ 15%) or incomplete RR (≤ 5%). 83 myocardial proteins were dysregulated through LC-MS/MS. Gene ontology enrichment analysis identified inflammation, complement and immune system activation as priming events of an incomplete RR and a better mitochondrial function underscoring complete RR. Kinetic metabolic modelling corroborated the lower ATP production capacity of incomplete RR patients. To uncover therapeutic targets, kinases were predicted from phosphoproteome data. Casein kinase 2 and DYRK1A were among the most dysregulated kinases in RR. DYRK1A was found to be inversely correlated with LVM regression (r = - 0.62). DYRK1A functional role (passive, maximal tension and Ca2+ sensitivity) was evaluated in skinned cardiomyocytes from Dyrk1a+/- mice and from AVS patients upon incubation with this kinase. Cardiomyocytes from mutant mice showed increased myofilamentary stiffness in response to stretch. Also, the raised myofilamentary stiffness of cardiomyocytes isolated from incomplete RR was normalised upon incubation with DYRK1A. Better myocardial bioenergetics may underscore a complete LVM regression. In turn, complement and immune-inflammatory pathways activation prime an incomplete response to AVR. DYRK1A emerges as a surrogate target to treat myocardial stiffness-driven diastolic dysfunction.