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

Article

关键词: FAILING HUMAN HEARTS;    SIGNAL TRANSDUCER;    CA2+ CHANNELS;    FAILURE;    CARDIOMYOPATHY;    ACTIVATION;    RECEPTORS;    KINASE;    GROWTH;    HYPERTROPHY;   

DOI  :  10.1161/CIRCULATIONAHA.115.017472

来源: SCIE

【 摘 要 】

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.

【 授权许可】

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