RRC ID 33968
Author Zhu X, Fang J, Jiang DS, Zhang P, Zhao GN, Zhu X, Yang L, Wei X, Li H.
Title Exacerbating Pressure Overload-Induced Cardiac Hypertrophy: Novel Role of Adaptor Molecule Src Homology 2-B3.
Journal Hypertension
Abstract The adaptor protein Src homology 2-B3 (SH2B3), which belongs to a subfamily of Src homology 2 proteins, is a broad inhibitor of growth factors and cytokine signaling in hematopoietic cells. However, the role of SH2B3 in nonhematopoietic systems, particularly cardiomyocytes, has not been defined. In this study, we observed noticeable increase in SH2B3 protein expression during pathological cardiac remodeling in both humans and rodents. Follow-up in vitro gain- and loss-of-function studies suggested that SH2B3 promotes the cardiomyocyte hypertrophy response. Consistent with the cell phenotype, SH2B3 knockout (SH2B3(-/-)) mice exhibited attenuated cardiac remodeling with preserved cardiac function after chronic pressure overload. Conversely, cardiac-specific SH2B3 overexpression aggravated pressure overload-triggered cardiac hypertrophy, fibrosis, and dysfunction. Mechanistically, SH2B3 accelerates and exacerbates cardiac remodeling through the activation of focal adhesion kinase, which, in turn, activates the prohypertrophic downstream phosphoinositide 3-kinase-AKT-mammalian target of rapamycin/glycogen synthase kinase 3β signaling pathway. Finally, we generated a novel SH2B3 knockout rat line and further confirmed the protective effects of SH2B3 deficiency on cardiac remodeling across species. Collectively, our data indicate that SH2B3 functions as a novel and effective modulator of cardiac remodeling and failure.
Volume 66(3)
Pages 571-81
Published 2015-9-1
DOI 10.1161/HYPERTENSIONAHA.115.05183
PMID 26101343
MeSH Adaptor Proteins, Signal Transducing Animals Blood Pressure / physiology* Cardiomegaly / genetics Cardiomegaly / metabolism* Humans Intracellular Signaling Peptides and Proteins / genetics Intracellular Signaling Peptides and Proteins / metabolism* Membrane Proteins Mice Mice, Knockout Myocardium / metabolism* Myocytes, Cardiac / metabolism* Proto-Oncogene Proteins / metabolism* Rats Signal Transduction / physiology
IF 7.713
Times Cited 17
Mice RBRC00993