beta(IV)-Spectrin regulates STAT3 targeting to tune cardiac response to pressure overload

Heart failure (HF) remains a major source of morbidity and mortality in the US. The multifunctional Ca2+/calmodulindependent kinase II (CaMKII) has emerged as a critical regulator of cardiac hypertrophy and failure, although the mechanisms remain unclear. Previous studies have established that the cytoskeletal protein beta(IV)-spectrin coordinates local CaMKII signaling. Here, we sought to determine the role of a spectrin-CaMKII complex in maladaptive remodeling in HF. Chronic pressure overload (6 weeks of transaortic constriction [TAC]) induced a decrease in cardiac function in WT mice but not in animals expressing truncated beta(IV)-spectrin lacking spectrin-CaMKII interaction (qv(3J) mice). Underlying the observed differences in function was an unexpected differential regulation of STAT3-related genes in qv(3J) TAC hearts. In vitro experiments demonstrated that beta(IV)-spectrin serves as a target for CaMKII phosphorylation, which regulates its stability. Cardiac-specific beta(IV)-spectrin-KO (beta(IV)-cKO) mice showed STAT3 dysregulation, fibrosis, and decreased cardiac function at baseline, similar to what was observed with TAC in WT mice. STAT3 inhibition restored normal cardiac structure and function in beta(IV)-cKO and WT TAC hearts. Our studies identify a spectrin-based complex essential for regulation of the cardiac response to chronic pressure overload. We anticipate that strategies targeting the new spectrin-based statosome will be effective at suppressing maladaptive remodeling in response to chronic stress.