Bombesin protects myocardium against ischemia/reperfusion injury via activation of the Keap1-Nrf2-HO-1 signaling pathway

Aims: It has been reported that some peptides released by the gastro-intestinal tract play important roles in the prevention of myocardial ischemia/reperfusion injury (MIRI). Bombesin (BN) is a biologically active peptide released by non-adrenergic non-cholinergic nerves on the gastric antrum mucosa controlled by the vagus nerve. However, there is a lack of reports on the impact of BN on MIRI. This study aimed to explore the influence of BN on MIRI and its underlying mechanism. Materials and methods: MIRI was induced by either 30 min of global ischemia in Langendorff perfused rat hearts, or by ligation of the descending coronary artery for 30 min in anesthetized Spraque-Dawley rats, and both were followed by 120 min reperfusion. Infarct size and left ventricular function were assessed, and lactate dehydrogenase (LDH), superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione (GSH) levels were measured spectrophotometrically, while cardiomyocyte apoptosis was detected by TUNEL assay. The content of BN in plasma was measured with enzyme-linked immunosorbent assays (ELISA). The expression of caspase 3, Kelch-like ECH-associated protein 1 (Keap1), nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) were quantified. Key findings: BN and vagus nerve stimulation improved cardiac contractile function and reduced myocardial infarct size, attenuated oxidative stress damage and myocardial cell apoptosis, increased the expression of Keap1, Nrf2, and HO-1. and these effects were blocked by using a BN receptor antagonist. Significance: BN provides protection against MIRI, and its underlying mechanism is through activation of the Keap1/Nrf2/HO-1 pathway. This research provides more reliable evidence for the "gut-heart axis dialogue" and explores potential therapeutic approaches for MIRI.