Critical Roles of STAT3 in beta-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; Long-Sheng Song; Xin-Yun Huang; Weinian Shou

doi:10.1161/CIRCULATIONAHA.115.017472

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

Journal article

Peer reviewed

Critical Roles of STAT3 in beta-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, …

Circulation (New York, N.Y.), Vol.133(1), pp.48-61

01/05/2016

DOI: 10.1161/CIRCULATIONAHA.115.017472

PMCID: PMC4698100

PMID: 26628621

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Abstract

Background beta-Adrenergic receptors (ARs) play paradoxical roles in the heart. On one hand, ARs augment cardiac performance to fulfill the physiological demands, but on the other hand, prolonged activations of ARs 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 AR-mediated signaling and function. Methods and Results We observed that STAT3 can be directly activated in cardiomyocytes by -adrenergic agonists. To follow up this finding, we analyzed AR function in cardiomyocyte-restricted STAT3 knockouts and discovered that the conditional loss of STAT3 in cardiomyocytes markedly reduced the cardiac contractile response to acute AR stimulation, and caused disengagement of calcium coupling and muscle contraction. Under chronic -adrenergic stimulation, Stat3cKO hearts exhibited pronounced cardiomyocyte hypertrophy, cell death, and subsequent cardiac fibrosis. Biochemical and genetic data supported that G(s) and Src kinases are required for AR-mediated activation of STAT3. Finally, we demonstrated that STAT3 transcriptionally regulates several key components of AR pathway, including (1)AR, protein kinase A, and T-type Ca2+ channels. Conclusions Our data demonstrate for the first time that STAT3 has a fundamental role in AR signaling and functions in the heart. STAT3 serves as a critical transcriptional regulator for AR-mediated cardiac stress adaption, pathological remodeling, and heart failure.

Cardiac & Cardiovascular Systems

Cardiovascular System & Cardiology

Life Sciences & Biomedicine

Peripheral Vascular Disease

Science & Technology

Details

Title: Subtitle: Critical Roles of STAT3 in beta-Adrenergic Functions in the Heart
Creators: Wenjun Zhang - From State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (W. Zhang, X.Q., Y.T., W.S.)
Xiuxia Qu - Peking Union Medical College Hospital
Biyi Chen - University of Iowa
Marylynn Snyder - Cornell University
Meijing Wang - University of Indianapolis
Baiyan Li - Riley Heart Res Ctr, Herman B Wells Ctr Pediat Res, Dept Pediat, Indianapolis, IN USA
Yue Tang - Peking Union Medical College Hospital
Hanying Chen - Indiana University
Wuqiang Zhu - University of Indianapolis
Li Zhan - University of Indianapolis
Ni Yin - Central South University
Deqiang Li - University of Indianapolis
Li Xie - Central South University
Ying Liu - University of Indianapolis
J. Jillian Zhang - Cornell University
Xin-Yuan Fu - University of Indianapolis
Michael Rubart - University of Indianapolis
Long-Sheng Song - University of Iowa
Xin-Yun Huang - Cornell University
Weinian Shou - Peking Union Medical College Hospital
Resource Type: Journal article
Publication Details: Circulation (New York, N.Y.), Vol.133(1), pp.48-61
DOI: 10.1161/CIRCULATIONAHA.115.017472
PMID: 26628621
PMCID: PMC4698100
NLM abbreviation: Circulation
ISSN: 0009-7322
eISSN: 1524-4539
Publisher: Lippincott Williams & Wilkins
Number of pages: 14
Grant note: CECARE R01HL081092 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) R01CA125568 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) HL81092; HL91525; HL090905; CA125568-05 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA SS2012AA023503 / 863 project U01AA023503 / NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Alcohol Abuse & Alcoholism (NIAAA) Indiana University School of Medicine Strategic Research Initiative
Language: English
Date published: 01/05/2016
Academic Unit: Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Internal Medicine
Record Identifier: 9984288722502771

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