Value of Label-Free Ubiquitin-Proteomic Analysis on Defining the Protective Mechanism of Valsartan against Doxorubicin-Induced Heart Failure

INTRODUCTION: The cardiotoxicity and subsequent Heart Failure (HF) induced by Doxorubicin (DOX) limit the clinical application of DOX. Valsartan (Val) is an angiotensin II receptor blocker that could attenuate the HF induced by DOX. However, the underlying mechanism of Val in this process is not fully understood. METHODS: In this study, we explored the cardio-protective mechanism of Val against DOX-induced cardiotoxicity using label-free ubiquitin-proteomic analysis. RESULTS: Results showed that 27 lysine-ubiquitination sites in 25 proteins were differentially expressed between DOX and DOX+Val treated groups. In addition, the levels of ubiquitin modification of the myosin family and Ankrd1 were upregulated post-Val. Val also in-creased ATP production and activated the Akt/mTOR pathway by regulating the sarcoplas-mic/endoplasmic reticulum calcium ATPase (SERCA2a) and cardiomyocyte calcium hemo-stasis. CONCLUSION: The results highlight the value of label-free ubiquitin-proteomic analysis in defining the molecular mechanism of Val against HF and may be helpful in the development of new therapeutic agents for HF via targeting molecules defined in this research.