Targeting the ubiquitin-proteasome system in heart disease: the basis for new therapeutic strategies.

SIGNIFICANCE: Novel therapeutic strategies to treat heart failure are greatly needed. The ubiquitin-proteasome system (UPS) affects the structure and function of cardiac cells through targeted degradation of signaling and structural proteins. This review discusses both beneficial and detrimental consequences of modulating the UPS in the heart. RECENT ADVANCES: Proteasome inhibitors were first used to test the role of the UPS in cardiac disease phenotypes, indicating therapeutic potential. In early cardiac remodeling and pathological hypertrophy with increased proteasome activities, proteasome inhibition prevented or restricted disease progression and contractile dysfunction. Conversely, enhancing proteasome activities by genetic manipulation, pharmacological intervention, or ischemic preconditioning also improved the outcome of cardiomyopathies and infarcted hearts with impaired cardiac and UPS function, which is, at least in part, caused by oxidative damage. CRITICAL ISSUES: An understanding of the UPS status and the underlying mechanisms for its potential deregulation in cardiac disease is critical for targeted interventions. Several studies indicate that type and stage of cardiac disease influence the dynamics of UPS regulation in a nonlinear and multifactorial manner. Proteasome inhibitors targeting all proteasome complexes are associated with cardiotoxicity in humans. Furthermore, the type and dosage of proteasome inhibitor impact the pathogenesis in nonuniform ways. FUTURE DIRECTIONS: Systematic analysis and targeting of individual UPS components with established and innovative tools will unravel and discriminate regulatory mechanisms that contribute to and protect against the progression of cardiac disease. Integrating this knowledge in drug design may reduce adverse effects on the heart as observed in patients treated with proteasome inhibitors against noncardiac diseases, especially cancer.