Intensive investigations into the pathophysiological significance of the
proteasome in the heart did not start until the beginning of the past decade but exciting progress has been made and summarized here as two fronts. First, strong evidence continues to emerge to support a novel hypothesis that
proteasome functional insufficiency represents a common pathological phenomenon in a large subset of
heart disease, compromises
protein quality control in heart muscle cells, and thereby acts as a major pathogenic factor promoting the progression of the subset of
heart disease to
congestive heart failure. This front is represented by the studies on the
ubiquitin-
proteasome system (UPS) in cardiac
proteinopathy, which have taken advantage of a transgenic mouse model expressing a fluorescence reporter for UPS proteolytic function. Second, pharmacological inhibition of the
proteasome has been explored experimentally as a potential therapeutic strategy to intervene on some forms of
heart disease, such as pressure-overload
cardiac hypertrophy, viral
myocarditis, and myocardial ischemic injury. Not only between the two fronts but also within each one, a multitude of inconsistencies and controversies remain to be explained and clarified. At present, the controversy perhaps reflects the sophistication of cardiac proteasomes in terms of the composition, assembly, and regulation, as well as the intricacy and diversity of
heart disease in terms of its etiology and pathogenesis. A definitive role of altered
proteasome function in the development of various forms of
heart disease remains to be established. This article is part of a Special Issue entitled The
26S Proteasome: When degradation is just not enough!