Wenjun Zhang1, Xiuxia Qu2, Biyi Chen2, Marylynn Snyder2, Meijing Wang2, Baiyan Li2, Yue Tang2, Hanying Chen2, Wuqiang Zhu2, Li Zhan2, Ni Yin2, Deqiang Li2, Li Xie2, Ying Liu2, J Jillian Zhang2, Xin-Yuan Fu2, Michael Rubart2, Long-Sheng Song2, Xin-Yun Huang2, Weinian Shou1. 1. 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.); Riley Heart Research Center, Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indianapolis, IN (W. Zhang, B.L., H.C., W. Zhu, L.Z., N.Y., D.L., L.X., Y.L., M.R., W.S.); Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City (B.C., L.-S.S.); Department of Physiology and Biophysics, Cornell University Weill Medical College, New York, NY (M.S., J.J.Z., X.-Y.H.); Department of Surgery, Indiana University School of Medicine, Indianapolis (M.W.); Department of Pharmacology, Harbin Medical University, Harbin, China (B.L.); Department of Heart Surgery, Xiangya 2nd Hospital, Central South University, Changsha, China (N.Y., L.X.); and Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis (X.-Y.F.). wenjun08@gmail.com wenzhang@iu.edu wnshou@gmail.com wshou@iu.edu. 2. 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.); Riley Heart Research Center, Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indianapolis, IN (W. Zhang, B.L., H.C., W. Zhu, L.Z., N.Y., D.L., L.X., Y.L., M.R., W.S.); Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City (B.C., L.-S.S.); Department of Physiology and Biophysics, Cornell University Weill Medical College, New York, NY (M.S., J.J.Z., X.-Y.H.); Department of Surgery, Indiana University School of Medicine, Indianapolis (M.W.); Department of Pharmacology, Harbin Medical University, Harbin, China (B.L.); Department of Heart Surgery, Xiangya 2nd Hospital, Central South University, Changsha, China (N.Y., L.X.); and Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis (X.-Y.F.).
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 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.
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 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.
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