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

Abstract

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,

Heat Shock Protein 90 as Therapeutic Target for CVDs and Heart Ageing

“…Thus, the development of HSPs-target agents able to specifically kill or suppress senescent or cancer cells would have significant therapeutic effects to provide healthy ageing, treat age-related diseases and improve resiliency. Indeed, certain HSPs inhibitors are undergoing clinical trials and others will be available for practitioners shortly (reviewed in [ 4 , 103 , 104 ]).…”

“…Recently, mitochondria have emerged as a key player in the progression of CVDs, thus making mitochondria-targeted therapies a promising approach in the prevention and treatment of CVDs [ 2 ]. In the context of different CVDs, mitochondrial protein quality controls systems have attracted wide attention [ 3 , 4 ].…”

With or without You: Co-Chaperones Mediate Health and Disease by Modifying Chaperone Function and Protein Triage

“…Conversely, there are diseases where activation of HSP70 to mimic thermal and immune preconditioning may be beneficial to outcomes [36,315]. We encourage the reader to look at in-depth reviews regarding the current landscape of targeting HSP70/90 function in cardiovascular disease [316,317], cancer [37,38,318], neurodegeneration [4,315], and inflammation [318,319]. More recent approaches include targeting the interactions between HSP90 and co-chaperones to inhibit chaperone function [320].…”

Linked biaromatic compounds as cardioprotective agents

“…[ 4–9 ] This concept is in direct accordance with the “multi‐target approach to cardioprotection” developed in the modern cardiology community. [ 4,10,11 ]…”

“…[4][5][6][7][8][9] This concept is in direct accordance with the "multi-target approach to cardioprotection" developed in the modern cardiology community. [4,10,11] Indeed, many of the cardioprotective strategies that have failed in the clinical setting have relied upon using a single-targeted approach, while a multitargeted approach directed to more than one molecular target or intracellular signaling pathways is being considered as more effective cardioprotective strategy, especially if one of the targets or signaling cascades is impaired due to the presence of a co-morbidity. The "multi-target effect" can be achieved by using either one active molecule with a multitargeting mechanism of action, [11] or a combination of compounds with different mechanisms.…”