[[beta].sub.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 [Ca.sup.2+]/calmodulin-dependent 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].sub.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].sub.IV]-spectrin lacking spectrin-CaMKII interaction ([qv.sub.3J] mice). Underlying the observed differences in function was an unexpected differential regulation of STAT3-related genes in [qv.sub.3J] TAC hearts. In vitro experiments demonstrated that [[beta].sub.IV]-spectrin serves as a target for CaMKII phosphorylation, which regulates its stability. Cardiac-specific [[beta].sub.IV]-spectrin-KO ([[beta].sub.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].sub.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.
IntroductionHeart failure (HF) represents a major burden on the US health care system, with 870,000 new cases annually and a total cost of $30.7 billion. By 2030, the incidence of [...]