Abstract 14892: Interaction of β IV -Spectrin/STAT3 is Responsible for Orienting Concentric versus Eccentric Cardiomyocyte Hypertrophy

Abstract

Cardiac hypertrophy is critical in the development of heart failure following chronic cardiac stress. 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. Previous work identified a role for the structural protein βIV-spectrin and its interaction with the transcription factor, STAT3, in coordinating hypertrophic profiles. Specifically, mice expressing truncated βIV-spectrin lacking interaction with the hypertrophic signaling molecule CaMKII (qv 3J mice) were resistant to βIV-spectrin degradation and maintained concentric hypertrophy and ejection fraction (EF) compared to WT following 6 weeks transaortic constriction (TAC). Alternatively, mutant βIV-spectrin mice (qv 4J ) lacking the STAT3/βIV-spectrin binding domain lead to cytosolic redistribution of STAT3 and associated with reduced EF and LV dilation consistent in eccentric remodeling, suggesting STAT3/βIV-spectrin is a key regulator of hypertrophic profiles and function. This relationship was further examined by adenoviral overexpression of the hypertrophic driver, MEK1/2, on isolated myocytes. As expected, MEK increased the width of WT myocytes, while qv 4J myocytes increased in length. However, application of STAT3 inhibitor S3I-201 on qv 4J myocytes reoriented these cells to growth in width. Additionally, in vivo application of S3I-201 to qv 4J mice was able to restore LV wall thickness and EF over 2 weeks, reinforcing STAT3 as a determinant of hypertrophic profiles. Evaluation of cardiac gene expression profiles from these backgrounds identified consistent elevations in microtubule subunits associated with eccentric growth patterns. Indeed, microtubule growth assays revealed qv 4J myocytes to express significantly enhanced microtubule stability which could be reversed through S3I-201 STAT3 inhibition. Together, these data identify a novel role for βIV-spectrin/STAT3 and microtubule stability in tuning specific hypertrophic profiles and cardiac function.