Cardiovascular disease remains the leading cause of death, accounting for 36% of all deaths in China [1]. Myocardial infarction (MI), one of the most common cardiovascular diseases threatening human health, usually leads to heart failure [2]. Early reperfusion of the ischemic myocardium is the most effective strategy to save the myocardium [3]. However, immediate restoration of blood flow in the ischemic region leads to lethal damage such as mitochondrial dysfunction, oxidative stress, Ca2+ overload, inflammation, and cell death, which are defined as myocardial ischemia-reperfusion injury (MIRI) [4]. Currently, there is no effective and widely accepted cure or drug for the treatment of MIRI [5]. Therefore, the search for a potential pharmacological agent continues to be the subject of intense investigation.

The Janus kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) pathway is known to be involved in the pathological processes of MIRI and MI and is activated in cardioprotection by ischemic pre- and post-treatment [4,[6], [7], [8]]. JAKs phosphorylate tyrosine residues in cognate STATs and exert cardioprotective effects by inhibiting the apoptotic cascade, specifically increasing the expression of the anti-apoptotic factor Bcl-2 and reducing the pro-apoptotic Bax [9]. In addition, STATs respond to cytokines such as the interleukin-6 and -10 families to drive nuclear transcription [10]. It has also been suggested that STAT3 can be localized to mitochondria and controls mitochondrial metabolism, the overexpression of which reduces reactive oxygen species (ROS) production, inhibits mitochondria-mediated apoptosis, and preserves the closure status of the mitochondrial permeability transition pore (mPTP) [[11], [12], [13]]. Pharmacological conditioning, such as opioids, has been shown to induce acute cardioprotection through tyrosine phosphorylation of JAK or STAT family members [14]. Thus, there is a tremendous opportunity to improve patient outcomes through novel therapeutic approaches targeting the JAK2/STAT3 pathway in MIRI.

Loganin, a monoterpene iridoid glycoside, is the major biologically active constituent of Cornus officinalis Sieb. et Zucc. Loganin exerts extensive pharmacological effects, including anti-inflammatory, anti-oxidant, anti-tumor, and anti-apoptotic [15]. The beneficial effects of loganin have been demonstrated in type 2 diabetes mellitus, a major risk factor for cardiovascular disease, where loganin exhibits potent blood glucose-lowering effects, neuroprotection, renal protection, and hepatoprotection [[16], [17], [18], [19], [20]]. Recently, direct evidence was provided for the cardioprotective property of loganin. Li et al. found that loganin reduced the production of inflammatory cytokines and suppressed the activation of NF-κB signaling in atherosclerosis [21]. At the same time, loganin protects the heart from angiotensin II-induced hypertrophy by inhibiting JAK2/STAT3 and NF-κB signaling pathways [22]. However, whether loganin also has cardioprotective effects against ischemic heart disease has not yet been investigated.

In the present study, we established an in vivo mouse model to determine the potential effects of loganin and identify its molecular mechanism in MIRI. We hypothesized that loganin inhibits cardiac oxidative stress and apoptosis through activation of the JAK2/STAT3 pathway.