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Ramping ubiquitinomics for the design of new sex-specific therapeutic strategies for aortic valve stenosis: Study
Fábio Trindade1, Ana Grego1, Daniel Seabra-Carvalho2
1RISE-Health, Departamento de Cirurgia e Fisiologia, Faculdade de Medicina, Universidade do Porto, Porto, Portugal.
Introduction And Objectives:
Aortic valve stenosis (AVS) is a growing healthcare burden and a paradigmatic example of sexual dimorphism in cardiovascular disease. Degenerative AVS results from valve fibrosis and calcification, affecting mainly women and men, respectively. Despite >20 years of clinical trials testing drugs such as statins, actaciguat, or vitamin K, aortic valve replacement (AVR) remains the only effective treatment. Evidence points to the relevance of protein ubiquitination in AVS progression, yet a holistic characterization of the ubiquitinome using mass spectrometry (MS) is lacking. Such an approach could uncover new targets for proteolysis-targeting chimeras (PROTACs), which remain underexplored in cardiovascular disease. RUBITAV aims to characterize the ubiquitinome landscape associated with fibrotic and calcific transformation of the valve and unveil sex-specific therapeutic targets. RUBITAV also aims to test the effect of modulating ubiquitinated proteins with PROTACs to mitigate fibrosis and calcification.
Methods:
Aortic valves will be collected from a sex-balanced and comorbidities-matched AVS cohort and dissected into morphologically normal, fibrotic, and calcified sections. Following protein extraction, ubiquitinated proteins will be enriched and quantified by MS. Putative sex-specific targets identified using bioinformatics will be modulated in vitro with PROTACs using valve interstitial cells maintained under pro-fibrotic or pro-calcific conditions. The primary outcome is defined as the % reduction in fibrosis (females) and calcification (males).
Results:
Not applicable.
Conclusion:
RUBITAV is expected to advance our understanding of the role of protein ubiquitination in AVS, identify new sex-specific therapeutic targets, and pave the way for the application of PROTACs in the treatment of AVS.
