Key result
Selective Hsp90 post-translational targeting emerges as a potential cardiac therapy that avoids cardiotoxicity.
Why the study?
Hsp90 interacts with pathogenic cardiac pathways, but small-molecule inhibitors can be cardiotoxic, prompting interest in targeting Hsp90 via post-translational modifications.
Does specific modulation of Hsp90 post-translational modifications improve pathological pathways in cardiac diseases?
Does specific modulation of Hsp90 post-translational modifications improve pathological pathways in cardiac diseases?
Targeting specific post-translational modifications of Hsp90 may offer a novel therapeutic approach for cardiac diseases while avoiding the recognized cardiotoxicity of systemic Hsp90 inhibition.
May support PTM-specific Hsp90 targeting to limit cardiotoxicity in cardiac disease; leaves open prospective validation before clinical adoption.
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 β (TGF-β) and mitogen activated kinase (MAPK) signaling to tumor necrosis factor α (TNFα), 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.
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Roberts et al. (2021) conducted a review in Cardiac Diseases. Hsp90 modulation was evaluated. Specific targeting of Hsp90 by modulation of post-translational modifications emerges as an attractive potential therapeutic strategy for cardiac diseases to avoid systemic cardiotoxicity.
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