Abstract 5572: Endothelial-Selective Deletion of Neuregulin-1 Leads to Impaired Tolerance of Ischemic Injury

Abstract

The neuregulin-1 (NRG)/erbB signaling axis is emerging as an important mediator of endothelial/myocyte crosstalk. We have previously shown that NRG can protect cardiac myocytes from apoptosis induced by hypoxic injury and that endothelial cells can provide this NRG in an ex vivo co-culture model. To extend this observation to an intact animal system, we have generated mice with inducible and endothelial-selective deletion of NRG. We hypothesized that animals with decreased endothelial NRG expression would be more susceptible to ischemic injury. Mice carrying a transgene for tamoxifen-inducible expression of cre recombinase under control of the Tie2 promoter were crossed with those carrying homozygously floxed NRG-1 genes. Serial echocardiographic measurements of cardiac function were performed before, during and after tamoxifen induction. There was no significant decrease in cardiac function following the completion of the induction (NRG knockout) protocol. Hearts from these mice underwent a global ischemia/reperfusion protocol in the Langendorff mode. Both resting and post-ischemic +/−dP/dT and left ventricular developed pressure were impaired in the animals with endothelial selective NRG deletion compared to non-induced transgenics or tamoxifen-induced controls. Hearts from the NRG deleted animals released more CPK and contained significantly more apoptotic nuclei compared to controls after ischemia/reperfusion, supporting the idea that endothelial-derived NRG can protect myocytes against apoptosis in vivo. Another mechanism by which loss of NRG may contribute to cardiac dysfunction in the setting of ischemia is by altering cardiac myocyte glucose uptake. We have shown that adult rat cardiomyocyte glucose uptake is significantly increased in response to NRG and that this response is abrogated partially by wortmannin, but completely by wortmannin plus compound C (an inhibitor of AMP-activated protein kinase), suggesting that both AKT and AMPK dependent pathways of glucose uptake may be activated by NRG in adult myocytes. Thus, we conclude that NRG plays an important role in preservation of cardiac myocyte function in vivo and that this may occur as a result of both protection against apoptosis and enhanced glucose metabolism.