Data_Sheet_1_SOCS3 Negatively Regulates Cardiac Hypertrophy via Targeting GRP78-Mediated ER Stress During Pressure Overload.docx

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.

压力超负荷诱导的心肌肥厚重塑是导致心力衰竭（heart failure, HF）的关键病理过程。细胞因子信号转导抑制因子3（Suppressor of cytokine signaling-3, SOCS3）已被证实可拮抗心肌肥厚与心功能损伤，但其具体作用机制仍未完全明确。本研究通过原代心肌细胞以及心脏特异性SOCS3敲除（SOCS3cko）或过表达小鼠，证实SOCS3的表达水平调控可影响肥厚刺激诱导的心肌肥厚、细胞凋亡及心功能障碍。研究发现，葡萄糖调节蛋白78（glucose regulatory protein 78, GRP78）是SOCS3的直接靶标；SOCS3过表达可通过促进GRP78的蛋白酶体降解，抑制心脏内质网（endoplasmic reticulum, ER）应激与线粒体自噬的激活，进而减轻心肌肥厚与细胞凋亡。综上，本研究揭示了SOCS3-GRP78介导的内质网应激通路，是持续性压力超负荷诱导的心肌肥厚向心力衰竭转化的全新机制，并提示调控该通路可为肥厚型心脏病提供新型治疗策略。