The Potential of Hsp90 in Targeting Pathological Pathways in Cardiac Diseases

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 beta (TGF-beta) and mitogen activated kinase (MAPK) signaling to tumor necrosis factor alpha (TNF alpha), G(s) and G(q) 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.

Automated summary

Hsp90 is a key molecular chaperone that interacts with numerous disease pathways in cells, making it a potential therapeutic target. While small-molecule inhibition of Hsp90 activity may have cardiac toxicity, targeting Hsp90 through modulation of post-translational modifications (PTMs) could be a more attractive therapeutic strategy.