Celastrol-type HSP90 modulators allow for potent cardioprotective effects
Henry Aceros1, Shant Der Sarkissian2, Mélanie Borie1
1Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada.
Life Sciences
|April 16, 2019
Summary
Celastrol and its analogs protect the heart from ischemic injury by modulating heat shock protein 90 (HSP90) activity. These compounds show promise for treating reperfusion injury.
Area of Science:
- Cardiovascular Research
- Molecular Biology
- Pharmacology
Background:
- Cardiac ischemic conditioning reduces injury via heat shock protein (HSP) modulation.
- Celastrol, an HSP90 modulator, previously demonstrated cardioprotection by activating HSPs and heme-oxygenase-1 (HO-1).
Purpose of the Study:
- To comparatively evaluate HSP90 modulators for cardioprotection.
- To characterize celastrol's structure-activity relationship for developing novel infarct-sparing agents.
Main Methods:
- In vitro cell culture of rat myocardial cells under ischemic/reperfusion (I/R) stress.
- Ex vivo Langendorff rat heart perfusion model to assess cardioprotective effects.
- Western blot and reporter gene assays to evaluate signaling pathways.
Main Results:
- Celastrol analogs efficiently induced cytoprotective HSP70 and HO-1, enhancing cell survival.
- Celastrol and analogs protected against ischemia and I/R injury, improving viability and reducing mitochondrial pore opening.
- Synthetic analogs demonstrated cardioprotective activity at lower concentrations than celastrol, activating multiple survival pathways.
Conclusions:
- The celastrol backbone is crucial for cardioprotection via HSP90 modulation.
- These compounds represent potential adjunct treatments for clinical management of I/R injury.
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