βIV-Spectrin regulates STAT3 targeting to tune cardiac response to pressure overload

Abstract

Heart failure (HF) remains a major source of morbidity and mortality in the US. The multifunctional Ca2+/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 βIV-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 βIV-spectrin lacking spectrin-CaMKII interaction (qv3J mice). Underlying the observed differences in function was an unexpected differential regulation of STAT3-related genes in qv3J TAC hearts. In vitro experiments demonstrated that βIV-spectrin serves as a target for CaMKII phosphorylation, which regulates its stability. Cardiac-specific βIV-spectrin-KO (βIV-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 βIV-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.

βIV-Spectrin/STAT3 complex regulates fibroblast phenotype, fibrosis, and cardiac function

“…Increased fibrosis and cardiac dysfunction in the setting of β IV -spectrin deficiency. Cardiac structure and function were first analyzed in 2 different models of β IV -spectrin deficiency: (a) qv 4J mice that carry a spontaneous mutation in Spnb4 resulting in expression of truncated β IV -spectrin lacking STAT3 binding (16,21); and (b) WT mice subjected to 6 weeks of transaortic constriction (TAC) to induce heart failure (acquired β IV -spectrin deficiency) (16). Echocardiography revealed a significant decrease in ejection fraction in qv 4J animals compared with WT, although not to the level observed in WT TAC mice ( Figure 1, A and B).…”

“…The observation of increased fibrosis in β IV -spectrin-deficient mice led us to ask whether CF function is directly affected by loss of β IV -spectrin. Although our previous work has elucidated a role for β IV -spectrin in regulating STAT3 signaling in myocytes (16), nothing is known about expression or function of the β IV -spectrin/STAT3 complex in CFs. Therefore, expression of the complex was analyzed in isolated primary CFs from adult WT (baseline and TAC) and qv 4J hearts by immunostaining.…”

“…To directly test the role of β IV -spectrin in observed changes in qv 4J fibroblasts, qv 4J CFs were transfected with a β IV -spectrin construct comprised of repeats 10 through the C-terminus (β IV , 10-C , containing putative STAT3 binding motif in repeat 15; ref. 16). Six days following transfection, qv 4J CFs expressing β IV , 10-C showed extranuclear STAT3 distribution, in contrast with the mostly nuclear localization observed in qv 4J expressing empty vector and WT ( Figure 5, A and B, and Supplemental Figure 6).…”

“…Importantly, loss of β IV -spectrin in response to chronic pressure overload promotes dysregulation of STAT3-dependent gene expression, increased fibrosis, and cardiac dysfunction in mice (16).…”

Wnt5a-induced M2 polarization of tumor-associated macrophages via IL-10 promotes colorectal cancer progression

“…Ma et al found that dysregulation of CaMKII in intestinal epithelial cells regulated colitis-associated colorectal carcinogenesis by enhancing STAT3 activation (45). Unudurthi et al showed that CaMKII was aberrantly activated in cardiac hypertrophy and heart failure, leading to degradation of βIV-spectrin, resulting in an increase of free STAT3 level (46). However, it was unclear in their work whether STAT3 was phosphorylated either by CaMKII or indirectly through another kinase.…”