Hypertrophic growth is a critical determinant of cardiac function in the development of heart failure. In pressure overload, hypertrophy is divided by early adaptive remodeling defined by concentric growth, while chronic hypertrophy associates with eccentric growth and loss in cardiac output. The mechanisms regulating this transition and the impact each profile has in influencing heart function are largely unknown. Importantly, previous work identified a role for the structural protein β IV -spectrin and its interaction with the transcription factor, STAT3, in coordinating hypertrophic profiles. Specifically, mice expressing truncated β IV -spectrin lacking interaction with the hypertrophic signaling molecule CaMKII ( qv 3J mice) were resistant to β IV -spectrin degradation and presented with sustained concentric hypertrophy and ejection fraction (EF) compared to WT following 6 weeks transaortic constriction (TAC). Alternatively, mutant β IV -spectrin mice ( qv 4J ) lacking the STAT3/β IV -spectrin binding domain had reduced EF and LV dilation, consistent with eccentric remodeling, suggesting STAT3/β IV -spectrin is a key regulator of hypertrophic profiles. To evaluate how STAT3 function was altered, we used the STAT3 activator, lipopolysaccharide, on isolated cardiomyocytes, which identified impaired STAT3 Ser727 phosphorylation in qv 4J myocytes compared to WT. The significance of this phosphorylation site was investigated using STAT3 Ser727 phospho-ablated mice (STAT3-S727A), which resulted in accelerated eccentric hypertrophy and HF in response to TAC. Furthermore, we identified elevated Ser727 phosphorylation in the qv 3J TAC mice, which present with sustained concentric growth, compared to WT mice which transition to eccentric growth. The relationship of STAT3/β IV -spectrin and hypertrophic orientation was further examined by adenoviral overexpression of the hypertrophic driver, MEK1/2, on isolated myocytes. While MEK increased the width of WT myocytes, STAT3-S727A and qv 4J myocytes increased in length. Together, these data identify a novel role for β IV -spectrin in coordinating STAT3 Ser727 phosphorylation to tune specific hypertrophic profiles in response to chronic stress and influencing cardiac function.
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