Abstract 15729: Neuregulin 1beta/erbb2 Signaling is Critical for Cardiac Recovery After Ischemic Injury
Introduction: ErbB2 plays a critical role in developing and adult heart. Neuregulin-1beta (Nrg) modulates PI3Kinase, MAPK, and Src/FAK signalling pathways in cardiac myocytes and thereby modulates cell survival and other phenotypes. Nrg is activated in the heart by ischemia/reperfusion injury, leading us to hypothesize that Nrg/ErbB modulates myocyte-matrix and myocyte-myocyte coupling and the response of the heart to ischemic injury at the intercalated disk.
Methods: Co-immunoprecipitation assays were performed to assess interactions between ErbB receptors and components of the FAC. Isolated mouse hearts were perfused according to the Langerdorff method, and subjected 15 min ischemia followed by 30 min of reperfusion (I/R). Hearts were fixed and immunostaining, histological and electron microscopy analysis was performed.
Results: Nrg induced ErbB2/ErbB4 co-immunoprecipitation with Src, FAK, p130CAS, and Paxilin in isolated myocytes. In isolated hearts subjected to I/R injury, phosphorylation of erbB2, FAK and Src were detected by immunoblot, and FAK, p130CAS, and ErbB2 were found to co-immunoprecipitate. Inhibition of ErbB2 in isolated hearts by a small molecule tyrosine kinase inhibitor (GW572016) prior to ischemia and during the reperfusion period significantly attenuated the % recovery in developed pressure at 30 min of reperfusion (control=58.67%±15.88 vs ErbB2 inhibition=13.13%±6.37; p=0.03). Sections from these hearts demonstrated that ErbB2 inhibition disrupted tissue structure and sarcomeric disorganization as detected by immnostaining for myomesin as well as electron micrographs. We also observed in both sham and ischemic heart treated with DMSO that intercalated discs retain normal structure with a clear undulated double membrane, whereas in heart treated with an ErbB2 inhibitor intercalated discs are disrupted.
Conclusions: Nrg/erbB signalling is activated by ischemia-reperfusion where it appears to mediate tissue recovery at least in part by regulating repair of the intercalated disk.
- © 2010 by American Heart Association, Inc.