Neuregulin receptors erbB2 and erbB4in failing human myocardiumDepressed expression and attenuated activation
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- 作者：S. Rohrbach ; B. Niemann ; R.-E. Silber and J. Holtz
- 关键词：Heart failure ; bcl– ; x splicing ; Bcl– ; xS/Bcl– ; xL ; apoptosis ; erbB2
- 刊名：Basic Research in Cardiology
- 出版年：2005
- 出版时间：May 2005
- 年：2005
- 卷：100
- 期：3
- 页码：240-249
- 全文大小：323 KB
文摘
Membrane–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 bcl–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: –25 % ; erbB4: –70 % ), their phosphorylationis reduced and bcl–x splicing is shifted towards 6.7–fold augmentationof proapoptotic Bcl–xS, compatible with attenuated erbB signaling.However, secreted and membrane–anchored neuregulin–1 isoforms, preferentiallyexpressed in microvascular endothelium, are induced and not loweredwith heart failure, while expression of erbB–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 bcl–xtowards enhanced formation of proapoptotic Bcl–xS, thereby contributing toenhanced apoptotic susceptibility of failing human myocardium.