| First Author | Zhang W | Year | 2016 |
| Journal | Circulation | Volume | 133 |
| Issue | 1 | Pages | 48-61 |
| PubMed ID | 26628621 | Mgi Jnum | J:239436 |
| Mgi Id | MGI:5828727 | Doi | 10.1161/CIRCULATIONAHA.115.017472 |
| Citation | Zhang W, et al. (2016) Critical Roles of STAT3 in beta-Adrenergic Functions in the Heart. Circulation 133(1):48-61 |
| abstractText | BACKGROUND: beta-Adrenergic receptors (betaARs) play paradoxical roles in the heart. On one hand, betaARs augment cardiac performance to fulfill the physiological demands, but on the other hand, prolonged activations of betaARs 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 betaAR-mediated signaling and function. METHODS AND RESULTS: We observed that STAT3 can be directly activated in cardiomyocytes by beta-adrenergic agonists. To follow up this finding, we analyzed betaAR function in cardiomyocyte-restricted STAT3 knockouts and discovered that the conditional loss of STAT3 in cardiomyocytes markedly reduced the cardiac contractile response to acute betaAR stimulation, and caused disengagement of calcium coupling and muscle contraction. Under chronic beta-adrenergic stimulation, Stat3cKO hearts exhibited pronounced cardiomyocyte hypertrophy, cell death, and subsequent cardiac fibrosis. Biochemical and genetic data supported that Galphas and Src kinases are required for betaAR-mediated activation of STAT3. Finally, we demonstrated that STAT3 transcriptionally regulates several key components of betaAR pathway, including beta1AR, protein kinase A, and T-type Ca(2+) channels. CONCLUSIONS: Our data demonstrate for the first time that STAT3 has a fundamental role in betaAR signaling and functions in the heart. STAT3 serves as a critical transcriptional regulator for betaAR-mediated cardiac stress adaption, pathological remodeling, and heart failure. |
