Abstract
Heat shock protein 90 (Hsp90) is a molecular chaperone that interacts with up to 10% of the proteome. The extensive involvement in protein folding and regulation of protein stability within cells makes Hsp90 an attractive therapeutic target to correct multiple dysfunctions. Many of the clients of Hsp90 are found in pathways known to be pathogenic in the heart, ranging from transforming growth factor (TGF-) and mitogen activated kinase (MAPK) signaling to tumor necrosis factor (TNF), Gs and Gq g-protein coupled receptor (GPCR) and calcium (Ca2+) signaling. These pathways can therefore be targeted through modulation of Hsp90 activity. The activity of Hsp90 can be targeted through small-molecule inhibition. Small-molecule inhibitors of Hsp90 have been found to be cardiotoxic in some cases however. In this regard, specific targeting of Hsp90 by modulation of post-translational modifications (PTMs) emerges as an attractive strategy. In this review, we aim to address how Hsp90 functions, where Hsp90 interacts within pathological pathways, and current knowledge of small molecules and PTMs known to modulate Hsp90 activity and their potential as therapeutics in cardiac diseases.
Highlights
Understanding the Heat shock protein 90 (Hsp90) interactome can help uncover the role it may play in these pathways, and how those roles could be changed to improve patient outcome in cardiomyopathy
It is without a doubt that Hsp90 is highly involved in these pathways through chaperone activity and stabilization that prevents degradation of signaling proteins, its numerous substrates pose a difficult task to fully understand the role of Hsp90 in each pathologic condition
While the effects of inhibiting Hsp90 have not been investigated in every context, many studies have investigated them, and can demonstrate the effect of inhibition on certain pathways
Summary
The primary roles of chaperones in the cell are to help stabilize proteins during folding, assisting them to reach their active conformation, and regulate their degradation. Chaperones are critical in the heat shock response by preventing protein unfolding and misfolding due to environmental stressors, intracellular stressors, and mutations [2] This stabilization allows cells to continue functioning in these suboptimal conditions. The Hsp chaperone family contains four isoforms in mammalian cells These isoforms are Hsp90α, Hsp90β, glucose response protein 94 (Grp94), and tumor necrosis factor type 1 receptor-associated protein (TRAP1) [6]. Hsp90α expression is inducible and regulated by heat shock factor 1 (HSF1), while Hsp90β is constitutively expressed [8] Together, these two isoforms make up 1–2% of cytosolic proteins in normal homeostasis, and up to 4–6% when a cell is stressed [9]. We will focus on the cytosolic Hsp (Hsp90α/β)
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