Critical roles of STAT3 in β-adrenergic functions in the heart

Wenjun Zhang, Xiuxia Qu, Biyi Chen, Marylynn Snyder, Meijing Wang, Baiyan Li, Yue Tang, Hanying Chen, Wuqiang Zhu, Li Zhan, Ni Yin, Deqiang Li, Li Xie, Ying Liu, J. Jillian Zhang, Xin Yuan Fu, Michael Rubart-von der Lohe, Long Sheng Song, Xin Yun Huang, Weinian Shou

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Background - 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 Ca2+ 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.

Original languageEnglish (US)
Pages (from-to)48-61
Number of pages14
JournalCirculation
Volume133
Issue number1
DOIs
StatePublished - Jan 5 2016

Fingerprint

STAT3 Transcription Factor
Adrenergic Agents
Adrenergic Receptors
Cardiac Myocytes
Heart Failure
Adrenergic Agonists
src-Family Kinases
Muscle Contraction
Cyclic AMP-Dependent Protein Kinases
Hypertrophy
Molecular Biology
Fibrosis
Cell Death
Animal Models
Cytokines
Calcium

Keywords

  • heart failure
  • receptors, adrenergic
  • receptors, G-protein-coupled
  • STAT3 transcription factor

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Critical roles of STAT3 in β-adrenergic functions in the heart. / Zhang, Wenjun; Qu, Xiuxia; Chen, Biyi; Snyder, Marylynn; Wang, Meijing; Li, Baiyan; Tang, Yue; Chen, Hanying; Zhu, Wuqiang; Zhan, Li; Yin, Ni; Li, Deqiang; Xie, Li; Liu, Ying; Zhang, J. Jillian; Fu, Xin Yuan; Rubart-von der Lohe, Michael; Song, Long Sheng; Huang, Xin Yun; Shou, Weinian.

In: Circulation, Vol. 133, No. 1, 05.01.2016, p. 48-61.

Research output: Contribution to journalArticle

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-von der Lohe, M, Song, LS, Huang, XY & Shou, W 2016, 'Critical roles of STAT3 in β-adrenergic functions in the heart', Circulation, vol. 133, no. 1, pp. 48-61. https://doi.org/10.1161/CIRCULATIONAHA.115.017472
Zhang, Wenjun ; Qu, Xiuxia ; Chen, Biyi ; Snyder, Marylynn ; Wang, Meijing ; Li, Baiyan ; Tang, Yue ; Chen, Hanying ; Zhu, Wuqiang ; Zhan, Li ; Yin, Ni ; Li, Deqiang ; Xie, Li ; Liu, Ying ; Zhang, J. Jillian ; Fu, Xin Yuan ; Rubart-von der Lohe, Michael ; Song, Long Sheng ; Huang, Xin Yun ; Shou, Weinian. / Critical roles of STAT3 in β-adrenergic functions in the heart. In: Circulation. 2016 ; Vol. 133, No. 1. pp. 48-61.
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AU - Qu, Xiuxia

AU - Chen, Biyi

AU - Snyder, Marylynn

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AU - Li, Baiyan

AU - Tang, Yue

AU - Chen, Hanying

AU - Zhu, Wuqiang

AU - Zhan, Li

AU - Yin, Ni

AU - Li, Deqiang

AU - Xie, Li

AU - Liu, Ying

AU - Zhang, J. Jillian

AU - Fu, Xin Yuan

AU - Rubart-von der Lohe, Michael

AU - Song, Long Sheng

AU - Huang, Xin Yun

AU - Shou, Weinian

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N2 - Background - 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 Ca2+ 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.

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