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Impact of Proteasome Subpopulations on Cardiac Remodeling

Final Report Summary - PROCARE (Impact of Proteasome Subpopulations on Cardiac Remodeling)

Primary objective of the study was to identify whether a seemingly non-essential single mechanism for protein degradation in the myocardium can be modulated to change the development of heart disease.
Heart disease is the number one cause of death in Europe and the world. Cardiac remodeling involving cardiac hypertrophy is associated with higher morbidity as well as mortality due to heart disease. Pathologic transformations of cardiac muscle mass are potentially influenced by the ubiquitin-proteasome system (UPS). At the heart of the UPS is the proteasome, which degrades specifically targeted proteins into peptides. The fellow has identified that the cardiac proteasomal core, the 20S proteasome, is a heterogenic group of highly similar multi-protein complexes with different functionality. During the development of cardiac hypertrophy, the assembly and thus the composition of 20S proteasome complexes is distinctly regulated. In consequence, proteasomal activities change non-uniformly. Gaining insights in the impact of this regulatory mechanism on cardiac remodeling was the main objective of the research project.
Investigations in a loss of function model of the mechanism in vivo showed severe deterioration of cardiac remodeling with accelerated pathogenesis, exacerbated hypertrophy and premature heart failure. In brief, the results emphasize a critical requirement for dynamic 20S proteasome regulation to cope with myocardial stress. Therefore, the assumption that 20S proteasome heterogeneity in the mammalian heart is non-essential requires reconsideration. For this reason, it was studied in detail whether absence of this mechanism may be associated with abnormal cardiac development or function prior to the induction of cardiac remodeling. The detailed characterization showed that hearts in the loss of function model are anatomically and functionally normal before the onset of cardiac remodeling. Thus, the results corroborate the notion that the mechanism is not essential for the unstressed myocardium.
Since a loss of function model of the mechanism deteriorated cardiac remodeling, it was hypothesized that a gain of function model potentially protects the heart against pathologic transformations eventually leading to heart failure. Therefore, a gain of function model was developed. As shown for the loss of function model, enhancing the mechanism had no impact on the unstressed myocardium. Remarkably, enhancing the mechanism indeed preserved cardiac function upon induction of cardiac remodeling. The enhancement was associated with differences in proteins, including those which are participating in muscle contraction and which are subject to proteasome degradation.
In conclusion, the study demonstrates that the investigated mechanism for the regulation of protein degradation is indeed non-essential for the heart unless processes are induced, which are associated with the development of heart disease and failure. Then, it protects the heart against the manifestation of heart disease and loss of function.