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

Autor:	Unudurthi SD; The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.; Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, Ohio, USA., Nassal D; The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.; Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, Ohio, USA., Greer-Short A; The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.; Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, Ohio, USA., Patel N; The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.; Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, Ohio, USA., Howard T; The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.; Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, Ohio, USA., Xu X; The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA., Onal B; The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.; Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, Ohio, USA., Satroplus T; The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.; Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, Ohio, USA., Hong D; The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.; Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, Ohio, USA., Lane C; The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.; Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, Ohio, USA., Dalic A; The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.; Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, Ohio, USA., Koenig SN; The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.; Department of Physiology and Cell Biology, and., Lehnig AC; The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.; Department of Physiology and Cell Biology, and., Baer LA; The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.; Department of Physiology and Cell Biology, and., Musa H; The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA., Stanford KI; The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.; Department of Physiology and Cell Biology, and., Smith S; The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.; Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, Ohio, USA., Mohler PJ; The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.; Department of Physiology and Cell Biology, and.; Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, Ohio, USA., Hund TJ; The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.; Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, Ohio, USA.; Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, Ohio, USA.
Jazyk:	angličtina
Zdroj:	The Journal of clinical investigation [J Clin Invest] 2018 Dec 03; Vol. 128 (12), pp. 5561-5572. Date of Electronic Publication: 2018 Nov 12.
DOI:	10.1172/JCI99245
Abstrakt:	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.
Databáze:	MEDLINE
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