Celastrol-type HSP90 modulators allow for potent cardioprotective effects

Publication date: Available online 12 April 2019Source: Life SciencesAuthor(s): Henry Aceros, Shant Der Sarkissian, Mélanie Borie, Louis-Mathieu Stevens, Samer Mansour, Nicolas NoiseuxAbstractAimsCardiac 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 methodsCombining 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 findingsFrom 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 (...
Source: Life Sciences - Category: Biology Source Type: research