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Life Sci. 2019 Jun 15;227:8-19. doi: 10.1016/j.lfs.2019.04.025. Epub 2019 Apr 12.

Celastrol-type HSP90 modulators allow for potent cardioprotective effects.

Author information

1
Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada.
2
Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada; Department of Surgery, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada.
3
Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada; Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada.
4
Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada; Department of Surgery, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada. Electronic address: nicolas.noiseux@umontreal.ca.

Abstract

AIMS:

Cardiac ischemic conditioning has been shown to decrease ischemic injury in experimental models and clinically. Activation of survival pathways leading to heat shock proteins (HSP) modulation is an important contributor to this effect. We have previously shown that celastrol, an HSP90 modulator, achieves cardioprotection through activation of cytoprotective HSP's and heme-oxygenase-1 (HO-1). This is the first comparative evaluation of several modulators of HSP90 activity for cardioprotection. Furthermore, basic celastrol structure-activity relationship was characterized in order to develop novel potent infarct sparing agents suitable for clinical development.

MAIN METHODS:

Combining in vitro cell culture using rat myocardial cell line exposed to ischemic and ischemia/reperfusion (I/R) stresses, and ex vivo Langendorff rat heart perfusion I/R model, we evaluated cardioprotective effects of various compounds. Selected signalling pathways were evaluated by western blot and reporter gene activation.

KEY FINDINGS:

From a variety of HSP90 modulator chemotypes, the celastrol family was most efficient in inducing cytoprotective HSP70 and HO-1 protein overexpression and cell survival in vitro. Celastrol and two synthetic analogs were protective against ischemia and prevented ischemia/reperfusion (I/R) injury when given as pre-treatment or at time of reperfusion, increasing viability and reducing mitochondrial permeability transition pore opening. Ex vivo experiments demonstrated that the two synthetic analogs show cardioprotective activity at lower concentrations compared to celastrol, with activation of multiple survival pathways.

SIGNIFICANCE:

Celastrol backbone is essential for cardioprotection through HSP90 activity modulation. These compounds hold promise as novel adjunct treatment to improve outcome in the clinical management of I/R injury.

KEYWORDS:

Cardiac conditioning; Cardioprotection; Celastrol; HSP90 inhibition; Ischemia/reperfusion injury

PMID:
30986447
DOI:
10.1016/j.lfs.2019.04.025
[Indexed for MEDLINE]

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