文摘
Membranex2013;bound and secreted neuregulin isoforms inducegrowth, survival and differentiation by activating erbB tyrosine kinase receptors.In cultured cardiomyocytes, erbB2 and erbB4 receptors regulate apoptosisby controlling bclx2013;x splicing, and conditional elimination of erbB2induces dilative cardiomyopathy in vivo. Therefore, we analyzed expressionand activation of erbB receptors in left ventricular myocardium from 32 heartfailure patients, from 10 organ donors, and from 15 heart failure patientsprior to and following unloading by ventricular assist devices. ErbB receptors,expressed in cardiomyocytes and noncardiomyocytes, are downregulatedin failing myocardium as mRNA (which is renormalized by hemodynamicunloading) and as protein (erbB2: x2013;25%; erbB4: x2013;70%), their phosphorylationis reduced and bclx2013;x splicing is shifted towards 6.7x2013;fold augmentationof proapoptotic Bclx2013;xS, compatible with attenuated erbB signaling.However, secreted and membranex2013;anchored neuregulinx2013;1 isoforms, preferentiallyexpressed in microvascular endothelium, are induced and not loweredwith heart failure, while expression of erbBx2013;inhibitory neuregulin isoformsor of autoinhibitory soluble erbB isoforms could not be demonstratedas potential causes of erbB receptor inhibition. We conclude that erbB receptorinactivation by unknown mechanisms results in altered splicing of bclx2013;xtowards enhanced formation of proapoptotic Bclx2013;xS, thereby contributing toenhanced apoptotic susceptibility of failing human myocardium.