Critical Roles of STAT3 in β-Adrenergic Functions in the Heart

dc.contributor.authorZhang, Wenjun
dc.contributor.authorQu, Xiuxia
dc.contributor.authorChen, Biyi
dc.contributor.authorSnyder, Marylynn
dc.contributor.authorWang, Meijing
dc.contributor.authorLi, Baiyan
dc.contributor.authorTang, Yue
dc.contributor.authorChen, Hanying
dc.contributor.authorZhu, Wuqiang
dc.contributor.authorZhan, Li
dc.contributor.authorYin, Ni
dc.contributor.authorLi, Deqiang
dc.contributor.authorLi, Xie
dc.contributor.authorLiu, Ying
dc.contributor.authorZhang, J. Jillian
dc.contributor.authorFu, Xin-Yuan
dc.contributor.authorRubart, Michael
dc.contributor.authorSong, Long-Sheng
dc.contributor.authorHuang, Xin-Yun
dc.contributor.authorShou, Weinian
dc.contributor.departmentDepartment of Pediatrics, IU School of Medicineen_US
dc.date.accessioned2017-05-03T17:13:11Z
dc.date.available2017-05-03T17:13:11Z
dc.date.issued2016-01-05
dc.description.abstractBACKGROUND: 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 hearts in both human patients and animal models. Our objective is to determine the potential regulatory roles of STAT3 in cardiac βAR-mediated signaling and function. METHODS AND RESULTS: 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, protein kinase A, and T-type Ca(2+) channels. CONCLUSIONS: Our data demonstrate 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 remodeling, and heart failure.en_US
dc.eprint.versionAuthor's manuscripten_US
dc.identifier.citationZhang, W., Qu, X., Chen, B., Snyder, M., Wang, M., Li, B., … Shou, W. (2016). Critical Roles of STAT3 in β-Adrenergic Functions in the Heart. Circulation, 133(1), 48–61. http://doi.org/10.1161/CIRCULATIONAHA.115.017472en_US
dc.identifier.urihttps://hdl.handle.net/1805/12439
dc.language.isoen_USen_US
dc.publisherAmerican Heart Associationen_US
dc.relation.isversionof10.1161/CIRCULATIONAHA.115.017472en_US
dc.relation.journalCirculationen_US
dc.rightsPublisher Policyen_US
dc.sourcePMCen_US
dc.subjectSTAT3 transcription factoren_US
dc.subjectHeart failureen_US
dc.subjectReceptorsen_US
dc.subjectG-protein-coupleden_US
dc.subjectReceptorsen_US
dc.subjectAdrenergicen_US
dc.titleCritical Roles of STAT3 in β-Adrenergic Functions in the Hearten_US
dc.typeArticleen_US
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