Phospho-Proteomic Analysis of Cardiac Dyssynchrony and Resynchronization Therapy

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Proteomics

Background:

• Cardiac dyssynchrony, common in heart failure, exacerbates patient morbidity and mortality.
• Cardiac resynchronization therapy (CRT) improves heart function by re-coordinating contractions, but its underlying molecular mechanisms are not fully understood.

Purpose of the Study:

• To investigate alterations in the cardiac phospho-proteome during dyssynchronous heart failure (HFdys).
• To determine how CRT modulates this unique phospho-proteome, focusing on Ser/Thr and Tyr phosphorylation.
• To identify key signaling pathways and kinases involved in HFdys and CRT response.

Main Methods:

• Analysis of phospho-enriched myocardium from canine models using mass spectrometry (MS).
• Comparison of phospho-proteomes across Control, HFdys, and CRT groups.
• Prediction of kinase targets for regulated phospho-sites and validation using western blot.

Main Results:

• 209 regulated phospho-sites were identified among 1761 total sites.
• HFdys demonstrated hyper-phosphorylation compared to Control and CRT groups.
• Tyrosine phosphorylation was significantly involved in signaling pathways altered by HFdys and further modulated by CRT.
• The kinase CK2 was specifically associated with phospho-sites normalized by CRT, suggesting its activation in HFdys and reversal by CRT.

Conclusions:

• Dyssynchronous heart failure significantly alters the cardiac phospho-proteome, involving tyrosine phosphorylation.
• CK2 signaling is activated in HFdys and reversed by CRT, indicating a potential therapeutic role.
• These findings elucidate novel signaling networks and identify CK2 as a potential target to augment CRT efficacy.