Therapeutic intervention with sinomenine and irisin to preserve cardiac function after ischaemia-reperfusion injury

Despite advancements in reperfusion therapy, myocardial ischaemia-reperfusion (IR) injury remains a major clinical challenge. This study investigated whether a novel dual-target pre-conditioning strategy using sinomenine and irisin could enhance myocardial resistance against IR injury. Ninety male Sprague-Dawley rats were utilized. Protocol 1 evaluated cardioprotection by assigning rats to Sham, IR, sinomenine, irisin or a combination of both agents, with pharmacological pre-treatments administered for 7 days prior to surgery. To model IR injury in vivo, animals underwent 30 min surgical ligation of the left anterior descending coronary artery followed by 24 h reperfusion. Combined pre-treatment exerted superior protection, significantly reducing infarct size (P = 0.0187) and serum cardiotroponin-I (P = 0.0028), while preserving myocardial architecture. Echocardiography and haemodynamic monitoring confirmed significantly enhanced ejection fraction (P < 0.0001), fractional shortening (P = 0.0002), developed pressure (P = 0.0001), +dP/dt (P < 0.0001), and -dP/dt (P = 0.0003), alongside reduced left ventricular internal diameter at end-systole (P < 0.0001) and end-diastole (P = 0.0004), as well as decreased end-diastolic pressure (P = 0.0128) in the combination group. Protocol 2 investigated mechanisms using mitochondrial division inhibitor 1 (Mdivi-1). Combined pre-treatment mitigated oxidative stress, suppressed pro-inflammatory cytokines and inhibited the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome, evidenced by significant reductions in NLRP3, apoptosis-associated speck-like protein containing a CARD, and cleaved Gasdermin D. Conversely, it significantly upregulated PTEN-induced putative kinase 1 (PINK1) and Parkin. Notably, Mdivi-1 abrogated these benefits, confirming that the enhanced protection is mediated through the activation of the PINK1/Parkin-dependent mitophagy pathway. These results suggest that pharmacological pre-conditioning with sinomenine and irisin offers a potent strategy against IR injury by modulating the mitophagy-pyroptosis axis.