Format

Send to

Choose Destination
J Clin Invest. 2018 Dec 3;128(12):5561-5572. doi: 10.1172/JCI99245. Epub 2018 Nov 12.

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

Author information

1
The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
2
Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, Ohio, USA.
3
Department of Physiology and Cell Biology, and.
4
Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, Ohio, USA.

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.

KEYWORDS:

Calcium signaling; Cardiology; Cytoskeleton; Heart failure

Supplemental Content

Full text links

Icon for American Society for Clinical Investigation Icon for PubMed Central
Loading ...
Support Center