BackgroundThe protective effect of Neuregulin-1 (NRG-1) on heart failure is well established. In this study, we assessed whether NRG-1 could protect the heart by mimicking the cardioprotective effects of ischaemic postconditioning (IP).MethodsWe used a myocardial reperfusion injury rat model in vivo to compare the cardioprotective effects of NRG-1(3 μg/kg, iv. at the onset of reperfusion) and IP. In Langendorff isolated heart perfusion experiments, we used the erythroblastic leukaemia viral oncogene homolog 4 (ErbB4) inhibitor AG1478, a phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 and a mitogen-activated protein/extracellular signal regulated kinase (MEK) inhibitor PD98059 to clarify whether the protective effects of NRG-1and IP depend on the NRG-1/ErbB4 signals and the reperfusion injury salvage kinase (RISK) pathway. Infarct size was detected by Evans blue and TTC. Apoptosis was detected by TUNEL assays. The expression of NRG-1/ErbB4 and downstream ERK1/2, AKT, AMPK and p70s6K were detected by western blotting. Hematoxylin/eosin (H&E) staining was used for histological analysis.ResultsWe found that NRG-1 and IP had similar effects on reducing myocardial infarct size and apoptosis in vivo. NRG-1 heart protein levels were upregulated in the IP group. Phosphorylation of AKT, ERK1/2 and ErbB4 were also increased in both the IP and NRG-1 groups. Furthermore, in Langendorff analyses, the ErbB4 inhibitor AG1478 suppressed the phosphorylation of ErbB4 and the RISK pathway and aggravated myocardial edema and fiber fracture, thereby inhibited the cardioprotective effects in both the IP and NRG-1 groups. For assessment of downstream signals, the PI3K inhibitor LY294002 and the MEK inhibitor PD98059 suppressed the phosphorylation of AKT and ERK1/2 respectively and abolished the cardioprotective effects induced by IP and NRG-1.ConclusionIn conclusion, both IP and NRG-1 could reduce infarct size and apoptosis through ErbB4-dependent activation of the RISK pathway in the same model; these results indicated the therapeutic potential of NRG-1 as a pharmacological postconditioning agent against myocardial reperfusion injury.

Neuregulin‐1 (NRG‐1) is reported to be cardioprotective through the extracellular‐regulated protein kinase (ERK) 1/2 pathway in myocardial ischaemia‐reperfusion injury (MIRI). NOX4‐induced ROS activated NLRP3 inflammasome and exacerbates MIRI. This study aims to investigate whether NRG‐1 can suppress NOX4 by ERK1/2 and consequently inhibit the NLRP3/caspase‐1 signal in MIRI. The myocardial infarct size (IS) was measured by TTC‐Evans blue staining. Immunohistochemical staining, real‐time quantitative PCR (RT‐qPCR) and Western blotting were used for detection of the factors, such as NOX4, ERK1/2, NLRP3, caspase‐1 and IL‐1β .The IS in the NRG‐1 (3 μg/kg, intravenous) group was lower than that in the IR group. Immunohistochemical analysis revealed NRG‐1 decreased 4HNE and NOX4. The RT‐qPCR and Western blot analyses revealed that NRG‐1 mitigated the IR‐induced up‐regulation of NOX4 and ROS production. Compared with the IR group, the NRG‐1 group exhibited a higher level of P‐ERK1/2 and a lower level of NLRP3. In the Langendorff model, PD98059 inhibited ERK1/2 and up‐regulated the expression of NOX4, NLRP3, caspase‐1 and IL‐1β, which exacerbated oxidative stress and inflammation. In conclusion, NRG‐1 can reduce ROS production by inhibiting NOX4 through ERK1/2 and inhibit the NLRP3/caspase‐1 pathway to attenuate myocardial oxidative damage and inflammation in MIRI.