Celastrol-type HSP90 modulators allow for potent cardioprotective effects

Aceros, H.; Sarkissian, Shant Der; Borie, M.; Stevens, Louis-Mathieu; Mansour, Samer; Noiseux, Nicolas

doi:10.1016/j.lfs.2019.04.025

Cited by 26 publications

(27 citation statements)

References 46 publications

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“…HSP90 activation is required for I/R cardioprotection. [ 27 ] Diabetes disrupts endogenous defense system in the tissue, HSPs are activated with the emergence of oxidative stress. Therefore, HSP90 expression also increases in diabetic heart tissue.…”

Section: Discussionmentioning

confidence: 99%

Thymoquinone attenuates doxorubicin‐cardiotoxicity in rats

Karabulut

Öztürk

Kaymak

et al. 2020

J Biochem & Molecular Tox

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Contrary to the fact that doxorubicin is a powerful chemotherapeutic agent for the treatment of neoplastic diseases, cardiotoxicity is too important to be ignored. Thymoquinone serves as a powerful free radical scavenger. In the study, the effects of thymoquinone against doxorubicin‐cardiotoxicity will be evaluated. Forty rats were divided into five groups. Group I: control group (n = 8); group II: olive oil group (n = 8); group III: thymoquinone group (n = 8); given 10 mg/kg thymoquinone intraperitoneally per day throughout the experiment; group IV: doxorubicin group (n = 8); injected with a single dose of 15 mg/kg ip doxorubicin on the 7th day of the experiment; group V: doxorubicin + thymoquinone group (n = 8); administered with 10 mg/kg thymoquinone per day during the experiment and 15 mg/kg doxorubicin ip on the 7th day. The experiment was planned for 14 days. Immunohistochemically, heat shock protein (HSP) 70 and HSP90, glucose‐regulated protein 78 (GRP78), caspase‐3 were stained. We made terminal deoxynucleotidyl transferase dUTP nick end labeling for apoptotic evaluation. Total oxidant status (TOS) levels and total antioxidant status (TAS) were measured in the heart tissue. Atrial natriuretic peptide (ANP) and pro‐B type natriuretic peptide (proBNP) were evaluated. In the study, HSP70, HSP90, GRP78, and caspase‐3 levels increased in group IV. TOS and TAS levels were significant compared to group I. Doxorubicin significantly increased ANP and NT‐proBNP levels. Thymoquinone revealed significant differences in these values. Thymoquinone can be an important cardioprotective agent against doxorubicin‐cardiotoxicity.

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Section: Discussionmentioning

confidence: 99%

Thymoquinone attenuates doxorubicin‐cardiotoxicity in rats

Karabulut

Öztürk

Kaymak

et al. 2020

J Biochem & Molecular Tox

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“…The results confirmed that compounds sharing structural similarities with celastrol and some known to target the interaction between HSP90 and its essential cofactors are compounds that are most efficient in inducing cell viability in the presence of physiological stressors as found during ischaemia. We identified and validated various celastrol analogues with the ability to activate multiple protective and cell survival pathways, and using ex vivo assays, we characterized their efficacy on preserving cardiac function and reducing myocardial damage during I/R injury (Aceros et al, 2019).…”

Section: The Hsp90 Inhibitor Celastrol Exhibits Potent Infarct-sparmentioning

confidence: 99%

Heat shock protein 90 inhibition and multi‐target approach to maximize cardioprotection in ischaemic injury

Sarkissian

Aceros

Williams

et al. 2020

British J Pharmacology

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Funding information Fondation de Stéphane Foumy of the Fondation du Grand Montréal; Fondation Marcel et Rolande Gosselin Despite several advances in medicine, ischaemic heart disease remains a major cause of morbidity and mortality. The unravelling of molecular mechanisms underlying disease pathophysiology has revealed targets for pharmacological interventions. However, transfer of these pharmcological possibilities to clinical use has been disappointing. Considering the complexity of ischaemic disease at the cellular and molecular levels, an equally multifaceted treatment approach may be envisioned. The pharmacological principle of 'one target, one key' may fall short in such contexts, and optimal treatment may involve one or many agents directed against complementary targets. Here, we introduce a 'multi-target approach to cardioprotection' and propose heat shock protein 90 (HSP90) as a target of interest. We report on a member of a distinct class of HSP90 inhibitor possessing pleiotropic activity, which we found to exhibit potent infarct-sparing effects. 1 | ISCHAEMIA AND REPERFUSION INJURY INVOLVE MULTIPLE PATHOPHYSIOLOGICAL PATHWAYS Myocardial infarction (MI) is a global leading cause of morbidity and mortality, and rapid implementation of reperfusion strategies accomplished by percutaneous coronary intervention, by thrombolytic therapy or by coronary artery bypass graft surgery is the "standard of care". While limiting infarct size expansion, paradoxically, reperfusion may result in worsening of tissue damage (Braunwald & Kloner, 1985; Kalogeris, Bao, & Korthuis, 2014). Therefore, the need for adjunct treatments to reduce infarct size expansion and to mitigate ischaemia/reperfusion (I/R) injury remain an important medical need. The cellular and molecular mechanisms by which tissue damage is initiated and propagated in the context of MI and I/R injury are complex and many-fold. These mechanisms include among other processes elevated levels of ROS with uncoupling of NOS (Kalogeris et al., 2014), opening of mitochondrial permeability transition pore (mPTP) causing release of cytochrome c (Garcia-Dorado, Ruiz-Meana,

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“…celastrol, cell apoptosis, fatty liver disease, nonalcoholic, Nrf2/HO-1 pathway, type 2 diabetes mellitus protecting cardiomyocytes against injury (Aceros et al, 2019). However, whether Cel plays a role in T2DM with NAFLD remains unclear.…”

Section: Introductionmentioning

confidence: 99%

“…Cel is a pentacyclic triterpenoid pigment with potent pharmacological activities including anti‐inflammation, immunosuppression, inhibition of angiogenesis, and antitumor (Zhan et al., 2018). Studies have shown that Cel can inhibit the production of inflammatory factors, such as IL‐1, TNF‐α, IL‐6, and IL‐8, and block the biological activities of heat shock protein 90 (Hsp90) by interacting with chaperones Cdc37 and p23 (Chadli et al., 2010), thereby protecting cardiomyocytes against injury (Aceros et al., 2019). However, whether Cel plays a role in T2DM with NAFLD remains unclear.…”

Section: Introductionmentioning

confidence: 99%