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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,

BACKGROUND AND PURPOSE Regression of left ventricular hypertrophy by moxonidine, a centrally acting sympatholytic imidazoline compound, results from a sustained reduction of DNA synthesis and transient stimulation of DNA fragmentation. Because apoptosis of cardiomyocytes may lead to contractile dysfunction, we investigated in spontaneously hypertensive rats (SHR), time‐ and dose‐dependent effects of in vivo moxonidine treatment on cardiac structure and function as well as on the inflammatory process and signalling proteins involved in cardiac cell survival/death. EXPERIMENTAL APPROACH 12 week old SHR received moxonidine at 0, 100 and 400 µg·kg−1·h−1, s.c., for 1 and 4 weeks. Cardiac function was evaluated by echocardiography; plasma cytokines were measured by elisa and hearts were collected for histological assessment of fibrosis and measurement of cardiac proteins by Western blotting. Direct effects of moxonidine on cardiac cell death and underlying mechanisms were investigated in vitro by flow cytometry and Western blotting. KEY RESULTS After 4 weeks, the sub‐hypotensive dose of moxonidine (100 µg) reduced heart rate and improved global cardiac performance, reduced collagen deposition, regressed left ventricular hypertrophy, inhibited Akt and p38 MAPK phosphorylation, and attenuated circulating and cardiac cytokines. The 400 µg dose resulted in similar effects but of a greater magnitude, associated with blood pressure reduction. In vitro, moxonidine inhibited norepinephrine‐induced neonatal cardiomyocyte mortality but increased fibroblast mortality, through I1‐receptor activation and differential effects on downstream Akt and p38 MAPK. CONCLUSIONS AND IMPLICATIONS While the antihypertensive action of centrally acting imidazoline compounds is appreciated, new cardiac‐selective I1‐receptor agonists may confer additional benefit.