Ana Grego, Cláudia Sousa-Mendes, Diana Martins, Carla Sousa, Ana Filipa Ferreira, Francisca Saraiva, Inês Alves, Guadalupe Espadas, Isabel Miranda, Adelino Leite-Moreira, Eduard Sabidó, António S Barros, Cristina Gavina, Rui Vitorino, Inês Falcão-Pires, Rita Nogueira-Ferreira, Fábio Trindade
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Abstract
Background: The treatment of aortic valve stenosis (AVS) remains limited to aortic valve replacement (AVR). No pharmacotherapy has yet proven efficacious, and its development is challenged by sexual dimorphism. Women display extensive valve fibrosis, and men present remarkably higher valve calcification. To accelerate the development of sex-personalised therapies, deeper molecular insights are needed. Hence, we aimed to characterise AVS sexual dimorphism using proteomics.
Methods: Fifty surgically excised valves (50% women) were homogenised, and the proteins were quantified by LC-MS/MS. The influence of differentially expressed proteins (DEPs) in sexual dimorphism was appraised using bioinformatics. DEPs were validated using immunohistochemistry, qRT-PCR and ELISA, with 30 additional valves.
Results: We quantified ~ 4,000 proteins and 76 DEPs between sexes. CD163, CD74, and NADPH oxidase-2 (NOX2) were more abundant in men's valves and central in a protein-protein interaction network. Functional enrichment analysis (FEA) supported increased lipoprotein binding and macrophage activation in men's valves, confirmed by increased CD74 + cell infiltration (immunohistochemistry). Aminopeptidase N, coagulation factor XIII, and metalloreductase STEAP4 were more abundant in men's valves at the transcript and protein levels. FEA indicated a women-specific dysregulation of spliceosomal proteins that may dictate a pro-fibrotic phenotype, which was observed histologically. A higher glutathione peroxidase-1/NOX2 ratio (ELISA) was found in women, suggesting increased protection against oxidative stress.
Conclusions: Proteomics confirms sexual dimorphism in AVS. Women displayed a higher degree of fibrotic remodelling, whereas men displayed greater immune cell infiltration and were less protected from oxidation, favouring calcification. Proteomics identified putative targets for a sex-personalised AVS modulation.
期刊介绍：
Clinical Proteomics encompasses all aspects of translational proteomics. Special emphasis will be placed on the application of proteomic technology to all aspects of clinical research and molecular medicine. The journal is committed to rapid scientific review and timely publication of submitted manuscripts.
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