Key result
RUBITAV protocol explores PROTACs as targeted sex-specific therapy in aortic valve stenosis.
Why the study?
Aortic valve stenosis exhibits sexual dimorphism and lacks effective drug treatments despite extensive clinical trials, with protein ubiquitination's role in AVS progression not holistically characterized.
Do PROTACs targeting sex-specific ubiquitinated proteins reduce fibrosis and calcification in valve interstitial cells derived from aortic valve stenosis?
Do PROTACs targeting sex-specific ubiquitinated proteins reduce fibrosis and calcification in valve interstitial cells derived from aortic valve stenosis?
This study protocol outlines a preclinical approach to characterize the ubiquitinome in aortic valve stenosis and investigate PROTACs as a novel, sex-specific therapeutic strategy to mitigate fibrosis and calcification.
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.
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Trindade et al. (2026) studied Aortic valve stenosis. Proteolysis-targeting chimeras (PROTACs) was evaluated on % reduction in fibrosis (females) and calcification (males). The RUBITAV study protocol aims to characterize the ubiquitinome in aortic valve stenosis and test PROTACs as a potential sex-specific therapeutic strategy; no results are yet available.
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