TY - JOUR
T1 - Critical roles of STAT3 in β-adrenergic functions in the heart
AU - Zhang, Wenjun
AU - Qu, Xiuxia
AU - Chen, Biyi
AU - Snyder, Marylynn
AU - Wang, Meijing
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, Michael
AU - Song, Long Sheng
AU - Huang, Xin Yun
AU - Shou, Weinian
N1 - Funding Information:
We thank Mark H. Soonpaa for critical review of the manuscript. This work was supported, in whole or in part, by NSFC81470446 and NSFC31401237 (to Drs Qu and Shou), 863 project SS2012AA023503 (YT), National Institutes of Health Grants HL81092 (to Dr Shou), HL91525 (to Dr Huang), HL090905 (to Dr Song), and CA125568-05 (to Dr Fu), and by Indiana University School of Medicine Strategic Research Initiative (to Dr Rubart) and CECARE (to Dr Shou).
Funding Information:
We thank Mark H. Soonpaa for critical review of the manuscript. This work was supported, in whole or in part, by NSFC81470446 and NSFC31401237 (to Drs Qu and Shou), 863 project SS2012AA023503 (YT), National Institutes of Health Grants HL81092 (to Dr Shou), HL91525 (to Dr Huang), HL090905 (to Dr Song), and CA125568-05 (to Dr Fu), and by Indiana University School of Medicine Strategic Research Initiative (to Dr Rubart) and CECARE (to Dr Shou).
Publisher Copyright:
© 2015 American Heart Association, Inc.
PY - 2016/1/5
Y1 - 2016/1/5
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.
AB - 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.
KW - STAT3 transcription factor
KW - heart failure
KW - receptors, G-protein-coupled
KW - receptors, adrenergic
UR - http://www.scopus.com/inward/record.url?scp=84953733202&partnerID=8YFLogxK
U2 - 10.1161/CIRCULATIONAHA.115.017472
DO - 10.1161/CIRCULATIONAHA.115.017472
M3 - Article
C2 - 26628621
AN - SCOPUS:84953733202
SN - 0009-7322
VL - 133
SP - 48
EP - 61
JO - Circulation
JF - Circulation
IS - 1
ER -