SOCS3 Negatively Regulates Cardiac Hypertrophy via Targeting GRP78-Mediated ER Stress During Pressure Overload
Shuang Liu1, Wen-Chang Sun2, Yun-Long Zhang3
1College of Basic Medical Sciences, Dalian Medical University, Dalian, China.
Insights
Suppressor of cytokine signaling-3 (SOCS3) protects the heart by degrading glucose regulatory protein 78 (GRP78), reducing endoplasmic reticulum stress and preventing heart failure progression. This highlights a new therapeutic target for hypertrophic heart disease.
Area of Science:
- Cardiology
- Molecular Biology
- Cellular Biology
Background:
- Pressure overload causes cardiac hypertrophy, a precursor to heart failure.
- Suppressor of cytokine signaling-3 (SOCS3) shows protective effects against cardiac hypertrophy, but its mechanisms are unclear.
Purpose of the Study:
- To elucidate the protective mechanisms of SOCS3 in pressure overload-induced cardiac hypertrophy.
- To investigate the role of SOCS3 in regulating endoplasmic reticulum (ER) stress and mitophagy in the heart.
Main Methods:
- Utilized primary cardiomyocytes and cardiac-specific SOCS3 knockout (SOCS3cko) and overexpression mouse models.
- Assessed cardiomyocyte hypertrophy, apoptosis, and cardiac dysfunction under hypertrophic stimuli.
- Investigated the interaction between SOCS3 and glucose regulatory protein 78 (GRP78) and its downstream effects on ER stress and mitophagy.
Main Results:
- SOCS3 levels directly influenced cardiomyocyte hypertrophy, apoptosis, and cardiac dysfunction.
- GRP78 was identified as a direct target of SOCS3.
- SOCS3 overexpression inhibited cardiomyocyte hypertrophy and apoptosis by promoting GRP78 proteasomal degradation, thereby reducing ER stress and mitophagy.
Conclusions:
- SOCS3-GRP78-mediated endoplasmic reticulum stress is a novel mechanism in the transition from cardiac hypertrophy to heart failure.
- Modulating the SOCS3-GRP78 pathway presents a potential therapeutic strategy for hypertrophic heart diseases.
Abstract:
Pressure overload-induced hypertrophic remodeling is a critical pathological process leading to heart failure (HF). Suppressor of cytokine signaling-3 (SOCS3) has been demonstrated to protect against cardiac hypertrophy and dysfunction, but its mechanisms are largely unknown. Using primary cardiomyocytes and cardiac-specific SOCS3 knockout (SOCS3cko) or overexpression mice, we demonstrated that modulation of SOCS3 level influenced cardiomyocyte hypertrophy, apoptosis and cardiac dysfunction induced by hypertrophic stimuli. We found that glucose regulatory protein 78 (GRP78) was a direct target of SOCS3, and that overexpression of SOCS3 inhibited cardiomyocyte hypertrophy and apoptosis through promoting proteasomal degradation of GRP78, thereby inhibiting activation of endoplasmic reticulum (ER) stress and mitophagy in the heart. Thus, our results uncover SOCS3-GRP78-mediated ER stress as a novel mechanism in the transition from cardiac hypertrophy to HF induced by sustained pressure overload, and suggest that modulating this pathway may provide a new therapeutic approach for hypertrophic heart diseases.
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