Pressure Overload Induces Cardiac Dysfunction and Dilation in Signal Transducer and Activator of Transcription 6-Deficient Mice

Background—Signal transducer and activator of transcription (STAT) proteins constitute a family of transcription factors that mediate many cytokine-induced responses. STAT6 is activated by angiotensin II and in rat hypertrophied hearts and in human hearts with dilated cardiomyopathy. This suggests that STAT6 may be involved in the pathogenesis of cardiac hypertrophy and heart failure. For this study we used STAT6-deficient (STAT6−/−) mice to examine the in vivo role of STAT6. Methods and Results—STAT6−/− hearts showed no morphological, histological, or functional defects. We examined left ventricular structural and functional remodeling 1 week after thoracic transverse aortic constriction (TAC). Western blot and immunohistochemical analyses showed increased STAT6 activity after TAC in the heart of wild-type mice. STAT6−/− mice showed a significant increase in end-diastolic left ventricular internal dimension accompanied by impaired contractility compared with wild-type mice but no differences in hypertrophic parameters. The number of terminal deoxynucleotidyl transferase–mediated biotin dUTP nick-end labeling–positive myocytes after TAC had increased in STAT6−/− compared with wild-type mice. Prolonged induction of tumor necrosis factor-&agr; (TNF-&agr;) mRNA was observed in STAT6−/− hearts, whereas TNF-&agr; mRNA was only transiently induced in wild-type mice. Tristetraprolin was induced after TAC in wild-type mice but not in STAT6−/− mice. Tristetraprolin reporter assay with the use of isolated neonatal cardiomyocyte indicated that the promoter was significantly activated by endothelin-1 in wild-type but not in STAT6−/− cardiomyocytes. The lack of promoter activation by endothelin-1 in STAT6−/− cardiomyocytes was rescued by forced expression of STAT6. Conclusions—STAT6 plays a protective role against hemodynamic stress in hearts.

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