The β_IV-Spectrin/STAT3 Complex Regulates the Orientation of Cardiac Hypertrophic Growth

Cardiac hypertrophy, defined as a stress-induced increase in heart mass/size, is a major risk factor for adverse cardiovascular events, including heart failure and arrhythmia. Within this general definition, the orientation of cell and organ growth varies considerably depending on stress type and duration, with important implications for cardiac function, yet little is known regarding the mechanisms that regulate hypertrophic orientation. Here, we evaluated the role of the cytoskeletal protein β_IV-spectrin and associated prohypertrophic STAT3 (signal transducer and activator of transcription 3) to direct the orientation of hypertrophic growth.

Transgenic mouse models with altered STAT3 signaling through modified interaction with its scaffolding partner β_IV-spectrin, or phospho-regulation of STAT3 directly, were evaluated at baseline, and after transaortic constriction, or aortocaval fistula. Unbiased screening of gene expression from these structurally divergent states was evaluated for pathways responsible for directing myocyte length/width. These pathways were tested in vitro using primary mouse myocytes and in vivo to tune growth patterns for therapeutic intervention.

Loss of β_IV-spectrin or direct STAT3 activation promoted a preferential increase in myocyte length over width, resulting in dilation of the left ventricular chamber (eccentric hypertrophy) and decreased systolic function. Conversely, preservation of β_IV-spectrin favored an increase in myocyte width without left ventricular dilation (concentric hypertrophy) and preserved systolic function in response to transaortic constriction or aortocaval fistula. Differential expression of genes associated with microtubules, including the trafficking kinesin motor, KIF20A (kinesin family member 20A), were identified in concentric versus eccentric hypertrophic states. In vitro assays revealed a relationship between β_IV-spectrin/STAT3 signaling, KIF20A expression, microtubule density, and spatial distribution of mRNA for the sarcomeric gene actc1. Finally, intervention with pharmacological STAT3 inhibition after chronic 6-week transaortic constriction successfully recovered concentric growth with improved systolic function.

These data identify a novel and pivotal role for β_IV-spectrin/STAT3 to modify microtubule properties and sarcomeric transcript distribution to direct myocyte geometry in response to chronic stress. These studies further illustrate the unique separation of hypertrophic growth and orientation as distinct pathways in cardiac remodeling.