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Exacerbating Pressure Overload-Induced Cardiac Hypertrophy: Novel Role of Adaptor Molecule Src Homology 2-B3
Xuehai Zhu1, Jing Fang1, Ding-Sheng Jiang1
1From the Division of Cardiothoracic and Vascular Surgery, Heart-Lung Transplantation Center, Sino-Swiss Heart-Lung Transplantation Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (X.Z., J.F., X.W.); Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (D.-S.J., P.Z., G.-N.Z., X.Z., L.Y., H.L.); and Cardiovascular Research Institute of Wuhan University, Wuhan, China (D.-S.J., P.Z., G.-N.Z., X.Z., L.Y., H.L.).
Insights
The adaptor protein SH2B3 (Src homology 2-B3) promotes pathological cardiac remodeling and hypertrophy. SH2B3 deficiency protects against heart failure, highlighting its role in cardiovascular disease.
Area of Science:
- Cardiovascular Biology
- Molecular Cell Biology
- Biochemistry
Background:
- The adaptor protein Src homology 2-B3 (SH2B3) is known to inhibit growth factor and cytokine signaling in hematopoietic cells.
- Its role in nonhematopoietic systems, specifically cardiomyocytes, remains largely undefined.
- Pathological cardiac remodeling is a significant contributor to heart failure.
Purpose of the Study:
- To investigate the role of SH2B3 in cardiomyocytes during pathological cardiac remodeling.
- To determine the molecular mechanisms by which SH2B3 influences cardiac hypertrophy and dysfunction.
- To evaluate the therapeutic potential of targeting SH2B3 in heart failure.
Main Methods:
- Analysis of SH2B3 protein expression in human and rodent cardiac remodeling models.
- In vitro gain- and loss-of-function studies in cardiomyocytes.
- Phenotypic analysis of SH2B3 knockout mice and cardiac-specific SH2B3 overexpression models under pressure overload.
- Generation of a SH2B3 knockout rat line.
- Mechanistic studies involving focal adhesion kinase and the PI3K-AKT-mTOR/GSK3β pathway.
Main Results:
- SH2B3 protein expression is upregulated during pathological cardiac remodeling.
- SH2B3 promotes cardiomyocyte hypertrophy in vitro.
- SH2B3 knockout mice show attenuated cardiac remodeling and preserved function after pressure overload.
- Cardiac-specific SH2B3 overexpression exacerbates hypertrophy, fibrosis, and dysfunction.
- SH2B3 activates focal adhesion kinase and the prohypertrophic PI3K-AKT-mTOR/GSK3β pathway.
- SH2B3 deficiency confers protection against cardiac remodeling across species.
Conclusions:
- SH2B3 is a novel and significant promoter of pathological cardiac remodeling and hypertrophy in cardiomyocytes.
- Targeting SH2B3 represents a potential therapeutic strategy for mitigating cardiac remodeling and failure.
- SH2B3 deficiency demonstrates protective effects against cardiac remodeling, confirmed across multiple species.
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.
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