Critical Roles of STAT3 in β-Adrenergic Functions in the Heart.
Critical Roles of STAT3 in β-Adrenergic Functions in the Heart.
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STAT3 在心脏 β-肾上腺素能功能中的关键作用。
DOI：
10.1161/circulationaha.115.017472
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发表时间：
2016-01-05
期刊：
影响因子：
37.8
通讯作者：
Shou W
中科院分区：
文献类型：
--
作者：
Zhang W;Qu X;Chen B;Snyder M;Wang M;Li B;Tang Y;Chen H;Zhu W;Zhan L;Yin N;Li D;Xie L;Liu Y;Zhang JJ;Fu XY;Rubart M;Song LS;Huang XY;Shou W
β-肾上腺素能受体（β AR）在心脏中起着矛盾的作用。一方面，β AR增强心脏性能以满足生理需求，但另一方面，β AR的长期激活产生有害作用，导致心力衰竭。信号转导子和转录激活子3（STAT 3）在许多组织中整合多种细胞因子信号传导途径中起动态作用。在人类患者和动物模型的衰竭心脏中观察到STAT 3的活化改变。我们的目标是确定STAT 3在心脏β AR介导的信号和功能中的潜在调节作用。我们观察到STAT 3可以被β-肾上腺素能受体激动剂直接激活。为了跟进这一发现，我们分析了心肌细胞限制性STAT 3敲除中的βAR功能，发现心肌细胞中STAT 3的条件性缺失显著降低了对急性βAR刺激的心脏收缩反应，并导致钙偶联和肌肉收缩的脱离。在慢性β-肾上腺素能刺激下，Stat 3cKO心脏表现出明显的心肌细胞肥大、细胞死亡和随后的心脏纤维化。生化和遗传学数据支持Gαs和Src激酶是β AR介导的STAT 3激活所必需的。最后，我们证实了STAT 3对βAR通路的几个关键组分，包括β1AR和PKA，以及T型Ca 2+通道的转录调控。我们的数据首次证明了STAT 3在心脏βAR信号传导和功能中具有重要作用。STAT 3是β AR介导的心脏应激适应、病理性重构和心力衰竭的关键转录调节因子。
β-adrenergic receptors (βARs) play paradoxical roles in the heart. On one hand, βARs augment cardiac performance to fulfill the physiological demands, but on the other hand, prolonged activations of βARs exert deleterious effects that result in heart failure. The signal transducer and activator of transcription 3 (STAT3) plays a dynamic role in integrating multiple cytokine signaling pathways in a number of tissues. Altered activation of STAT3 has been observed in failing heart in both the human patients and animal models. Our objective is to determine the potential regulatory roles of STAT3 in cardiac βAR-mediated signaling and function. We observed that STAT3 can be directly activated in cardiomyocytes by β-adrenergic agonists. To follow up this finding, we analyzed βAR function in cardiomyocyte-restricted STAT3 knockouts and discovered that the conditional loss of STAT3 in cardiomyocytes markedly reduced the cardiac contractile response to acute βAR stimulation, and caused disengagement of calcium coupling and muscle contraction. Under chronic β-adrenergic stimulation, Stat3cKO hearts exhibited pronounced cardiomyocyte hypertrophy, cell death, and subsequent cardiac fibrosis. Biochemical and genetic data supported that Gαs and Src kinases are required for βAR-mediated activation of STAT3. Finally, we demonstrated that STAT3 transcriptionally regulates several key components of βAR pathway, including β1AR and PKA, and T-type Ca2+ channels. Our data demonstrates for the first time that STAT3 has a fundamental role in βAR signaling and functions in the heart. STAT3 serves as a critical transcriptional regulator for βAR-mediated cardiac stress adaption, pathological remodelling and heart failure.