Abstract P2068: β Iv -spectrin/stat3 Are Responsible For Concentric Versus Eccentric Cardiac Hypertrophy

Abstract

Hypertrophy is critical to development of heart failure following cardiac stress. In pressure overload, hypertrophy is divided by early concentric and chronic eccentric orientations, however, the mechanisms regulating this transition and the impact on heart function are largely unknown. Previous work identified 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 kinase CaMKII ( qv 3J mice) resisted β IV -spectrin degradation and maintained concentric hypertrophy and systolic function compared to WT following 6 weeks transaortic constriction (TAC). Alternatively, mutant β IV -spectrin mice lacking the β IV -spectrin/STAT3 binding domain ( qv 4J ) expressed reduced EF and LV dilation, consistent with eccentric remodeling, suggesting β IV -spectrin/STAT3 is a regulator of cardiac profiles. This relationship was examined by adenoviral expression of the hypertrophic driver MEK1/2 on isolated myocytes, where MEK increased the width of WT cells but length in qv 4J . Notably, application of STAT3 inhibitor S3I-201 on qv 4J myocytes restored growth in width. Additionally, in vivo delivery of S3I-201 to WT mice after 6 weeks TAC reduced LV dilation and recovered systolic function. To enable hypertrophy, recent work identified the need for microtubules to traffic and locally translate sarcomeric transcripts. Therefore, we tested the hypothesis that β IV -spectrin/STAT3 direct orientation by altering microtubule stability and sarcomeric transcript trafficking. Isolated myocytes from WT and qv 4J mice were treated with the microtubule depolymerizing drug Nocodazole and then washed to evaluate microtubule repolymerization. Microtubules restored faster in qv 4J myocytes but could be reduced to WT levels by treating with S3I-201. Furthermore, localization of the sarcomeric gene, actc1 (α-actinin) by RNAScope showed more peripheral localization in qv 4J myocytes, compared to WT, and was normalized by S3I-201. Together, these data identify β IV -spectrin/STAT3 as modulators of microtubule dynamics, sarcomeric transcript distribution, hypertrophic orientation, and systolic function.