[Effect of neuregulin-1 on cardiac glucose metabolism in rats with experimental myocardial infarction].

Objective: To investigate the effect of neuregulin-1(NRG-1) on cardiac glucose metabolism in Sprague Dawley (SD) rats with experimental myocardial infarction (MI). Methods: Adult male SD rats were randomly divided into three groups: the sham-operated group, MI group, and MI+NRG1 group. The rat MI model was established via ligation of the left anterior descending coronary artery. Two weeks after operation, echocardiography was performed, MI rats with left ventricular ejection fraction (LVEF) between 0.3-0.5 were selected and randomly assigned to MI group and MI+NRG-1 group. Rats in MI+NRG-1 group were treated with recombinant human NRG-1β (100 μg/kg) via tail vein at 2 weeks after operation (twice per week for 6 weeks); while rats in sham-operated group and MI group received equal volume of physiological saline. By the end of administration, echocardiography and small animal positron emission tomography (PET) were performed to detect cardiac function and myocardial glucose uptake. Myocardial morphology and collagen volume fraction, cardiomyocyte apoptosis and reactive oxygen species (ROS) production were evaluated by histopathologic analysis. Myocardial pyruvate dehydrogenase (PDH) and citrate synthase (CS) activity, as well as ATP production were detected by commercial kits. The mRNA and protein expression levels of NRG-1, p-ErbB4, and key factors involved in glucose metabolism (including Glut-4, HK2, PDK4, PDH, CS) were detected by quantitative real-time PCR (qRT-PCR) and Western blot assay, respectively. Results: With the MI model successfully established, the left ventricular ejection fraction(LVEF) and left ventricular shortening fraction(LVFS) were significantly lower in MI group and MI+NRG-1 group than that in sham group (both P 0.05). After 6 weeks of NRG-1β intervention, the LVEF and LVFS were significantly higher in MI+NRG-1 group than in MI group (both P<0.01). By the end of experiment, PET imaging showed that the mean standardized uptake value (SUVmean) were lower in MI+NRG-1 group than in the sham group (4.06±0.28 vs. 5.18±0.37, P<0.01), while significantly higher than that in MI group (4.06±0.28 vs.2.86±0.49, P<0.01). Histopathological analysis showed that compared with MI group, rats in MI+NRG-1 group exhibited significantly decreased left ventricle collagen volume fraction ((7.83±1.24) % vs. (18.31±3.58) %, P<0.01), cardiomyocyte apoptosis((37.98±4.26)% vs. (67.04±5.38)%, P<0.01), and DHE fluorescence intensity(0.057 28±0.007 06 vs. 0.076 94±0.008 46, P<0.01), indicating that NRG-1β could reduce ROS production. PDH activity, CS activity, and ATP production were significantly higher in MI+NRG-1 group than in MI group (all P<0.05). qRT-PCR demonstrated an upregulated Glut-4, HK2 and CS, but downregulated PDK4 mRNA expression in MI+NRG-1 group compared with MI group (all P<0.01). Western blot assay showed significantly higher protein expression of NRG-1, p-ErbB4, Glut-4, HK2, PDH, CS in MI+NRG-1 group than in MI group (all P<0.01). Conclusion: NRG-1 could improve glucose uptake and utilization in myocardium by activating phosphorylation of myocardial ErbB4 receptor in MI rats, thus providing a therapeutic option for improving energy metabolism after MI.