Mechanisms underlying altered ubiquitin-proteasome system activity during heart failure and pharmacological interventions

Heart failure (HF) is a refractory disease with a global prevalence that is continuously increasing. The mechanisms underlying the pathogenesis of HF are multi-faceted, intricate, and not yet fully elucidated. Appropriate levels of protein turnover are essential for maintaining cardiac homeostasis and, accordingly, compromised protein degradation systems can significantly contribute to heart disease. The ubiquitin-proteasome system (UPS) modulates the structure and function of cardiac cells by facilitating the degradation of signaling and structural proteins. Research in the preceding decade has focused on elucidating the role of the UPS in the context of cardiovascular physiology and pathophysiology. A comprehensive understanding of the UPS status and the underlying mechanisms contributing to its potential dysregulation in HF is imperative for developing targeted therapeutic interventions. Previous research has identified several novel interventions involving components of the UPS and several have been adapted for HF therapy. In this review, we summarize the mechanisms underlying altered UPS activity in HF and provide an outline of UPS regulators that affect the progression of HF. Additionally, the potential for small molecules to intervene in UPS function in HF is discussed.