Dataset Information

Characterization of the human myocardial phosphoproteome in aortic stenosis patients with complete or incomplete reverse remodeling

ABSTRACT: Aortic valve stenosis (AS) is a serious condition characterized by the progressive narrowing of the aortic valve, associated with a continuous rise in left ventricle pressure overload. Currently, aortic valve replacement (AVR) remains as the definitive treatment for AS, since an immediate dissipation of left ventricle pressure overload is achieved with this intervention. Upon AVR, a myocardial response, known as reverse remodeling (RR), is set into motion, characterized by regression of hypertrophy and cardiac function normalization. In spite of the AVR benefits, cardiologists still face the problem of RR variability, with some patients displaying a complete and others an incomplete recovery, for instance, due to prevailing hypertrophy. Patients with incomplete RR are at higher risk of developing diastolic dysfunction and, ultimately, heart failure. Myocardial biopsies, available during AVR, provide a wealth of information through its molecular characterization. Particularly, the characterization of the myocardium phosphoproteome may help identify dysregulated pathways underlying an incomplete RR. Moreover, kinase prediction can also be useful to identify new molecular targets aiming at improving the phenotype of this subset of patients. Hence, we aimed to characterize, for the first time, the myocardial phosphoproteome from AS patients with complete and incomplete RR. To fulfil this task, we followed a shotgun LC-MS/MS approach using an Orbitrap instrument, after TiO2-based phosphopeptide enrichment. Phosphopeptides were identified and quantified through a MaxQuant label-free quantification approach (FDR 1%).

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Heart, Myocardium, Left Ventricle

DISEASE(S): Aortic Valve Stenosis

SUBMITTER: Fábio Trindade

LAB HEAD: Rui Vitorino

PROVIDER: PXD015498 | Pride | 2025-10-20

REPOSITORIES: Pride

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Publications

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

Trindade Fábio F Almeida-Coelho João J Sousa-Mendes Cláudia C Saraiva Francisca F Arbonés Maria L ML Leite-Moreira Adelino A Vitorino Rui R Falcão-Pires Inês I

Basic research in cardiology 20250706 5

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 ca ...[more]

PMID: 40618317

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Project description:Located at the junction of left ventricle and ascending aorta, aortic root is a central cardiovascular structure consisting of aortic valve and coronary ostium that are essential for systemic and coronary circulation, respectively. Malformations of aortic valve and coronary ostium are common birth defects and may occur together in human patients, leading to complex complications including aortic valve stenosis, myocardial ischemia, heart failure and sudden cardiac death. Despite of their physiological and clinical significances, the developmental and molecular mechanisms by which coordinate the formation of aortic valve and coronary ostium remain poorly understood. Here we report that SOX17 (SRY-box 17) is an essential transcription factor required for the maturation of aortic root, as well as the patterning of aortic valve and coronary ostium. We show in mouse that deletion of Sox17 in the aortic root endothelium results in defective aortic valve with underdeveloped non-coronary leaflet (NCL) or bicuspid aortic valve (BAV) without NCL. The valve defects are accompanied by misplaced left coronary ostium that reduces coronary blood flow, leading to myocardial hypoxia and death of embryos. Mechanistically, deletion of Sox17 decreases the expression of Pdgfb (Platelet derived growth factor, B polypeptide) in the aortic root endothelium and the PDGF growth signaling in the NCL mesenchyme and aortic root smooth muscle, both of which are derived from the second heart field (SHF) cardiomyocyte precursors. Furthermore, the deletion upregulates the expression of Ctgf (Connective tissue growth factor) and the extracellular matrix (ECM) genes, whereas downregulates the vascular smooth muscle genes, in the forming aortic root. Together, these findings support a developmental disease mechanism in which delayed growth and maturation of aortic root, due to lack of SOX17-PDGF/CTGF signaling, contributes to BAV and CAAs, two common congenital cardiovascular defects.

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