TGFβ Receptor Activation Enhances Cardiac Apoptosis Via SMAD Activation and Concomitant NO Release
TGFβ Receptor Activation Enhances Cardiac Apoptosis Via SMAD Activation and Concomitant NO Release
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DOI：
10.1002/jcp.22619
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发表时间：
2011-10-01
影响因子：
5.6
通讯作者：
Euler, Gerhild
中科院分区：
文献类型：
--
作者：
Heger, Jacqueline;Warga, Bjoern;Euler, Gerhild
在从代偿性肥大向心力衰竭转变期间，转化生长因子β（TGF β）表达在心肌中被诱导。在心肌细胞中，用TGF β刺激导致收缩功能受限和细胞凋亡增强。一氧化氮（NO）也可诱导细胞凋亡，影响心脏功能。因此，我们想知道NO是否与TGF β诱导的细胞凋亡有因果关系。在成年大鼠离体心室肌细胞中，TGF β 1可增加NO释放，NOS抑制剂ETU可抑制NO释放，而iNOS抑制剂（1400 W）或nNOS抑制剂（TFA）则无此作用。此外，TGF β诱导的细胞凋亡被ETU和ODQ阻断，但不被1400 W或TFA阻断。内皮NOS参与TGF β诱导的NO形成和凋亡的假设得到了eNOS在丝氨酸1177处磷酸化增加和TGF β不增加eNOS KO小鼠中NO释放的事实的支持。此外，TGF β诱导的细胞凋亡，NO的形成，SMAD结合活性和SMAD 2磷酸化被阻断的TGF β受体拮抗剂，但只有细胞凋亡和NO的形成可以被阻断ETU。TGF β刺激后SMAD 7的表达增加，并被TGF β受体拮抗剂阻断，但用ETU阻断NO合酶后则不然。结论：在心肌细胞中，TGF β诱导的细胞凋亡是通过TGF β受体活化介导的，TGF β受体活化同时激活SMAD转录因子和eNOS/NO/sGC途径。这两种途径都是TGF β诱导细胞凋亡所必需的。这揭示了心脏NO释放的新途径，并将NO确定为TGF β介导的心力衰竭进展的可能贡献者。J.细胞。226：2683-2690，2011。(C)2010 Wiley-Liss，Inc.
Transforming growth factor beta(TGF beta) expression is induced in the myocardium during transition from compensated hypertrophy to heart failure. In cardiomyocytes, stimulation with TGF beta results in restricted contractile function and enhanced apoptosis. Nitric oxide (NO) also induces apoptosis and influences cardiac function. Therefore, we wanted to know whether NO is causally involved in TGF beta-induced apoptosis. In isolated ventricular cardiomyocytes of adult rat incubation with TGF beta(1) increased NO release which was inhibited by NOS inhibitor ETU but not with iNOS inhibitor (1400 W) or nNOS inhibitor (TFA). In addition, TGF beta-induced apoptosis was blocked with ETU and ODQ, but not with 1400 W or TFA. The consequent assumption that endothelial NOS is involved in TGF beta-induced NO formation and apoptosis was supported by increased phosphorylation of eNOS at serine 1177 and by the fact that TGF beta did not increase NO release in eNOS KO mice. Furthermore, TGF beta-induced apoptosis, NO formation, SMAD binding activity and SMAD2 phosphorylation were blocked by a TGF beta receptor antagonist, but only apoptosis and NO formation could be blocked with ETU. Expression of SMAD7 was increased after TGF beta stimulation and blocked with TGF beta receptor antagonist but not after blocking NO synthase with ETU. Conclusion: In cardiomyocytes TGF beta-induced apoptosis is mediated via TGF beta receptor activation that concomitantly activates SMAD transcription factors and the eNOS/NO/sGC pathway. Both of these pathways are needed for apoptosis induction by TGF beta. This reveals a new pathway of cardiac NO release and identifies NO as a possible contributor to heart failure progression mediated by TGF beta. J. Cell. Physiol. 226: 2683-2690, 2011. (C) 2010 Wiley-Liss, Inc.