PGAM2调控心肌肥厚的作用及机制

Cardiac hypertrophy is an important factor leading to heart failure. Prevention of cardiac hypertrophy is an important way to prevent the occurrence of heart failure. It has been reported that PGAM2 induced early heart failure through modulation the energy metabolism. However, whether PGAM2 is involved in the regulation of cardiac hypertrophy and the relative mechanism is unknown. In our preliminary work, we found PGAM2 expression was elevated significantly in hypertrophic myocytes, and knockdown PGAM2 could attenuate cardiac hypertrophy significantly, suggesting that PGAM2 was a key factor involved in the regulation of cardiac hypertrophy. Meantime, we found that the heat shock protein 90 (HSP90) could interact with PGAM2, and be regulated by PGAM2. It has been reported PPARα and NFκB were the downstream effect factors of HSP90, and involved in cardiac hypertrophy. So we hypothesize that PGAM2 involved in the regulation of cardiac hypertrophy through interaction with HSP90, and regulating the downstream effect factors PPARα and NFκB. In this study, we aim to clarify the role of PGAM2 in cardiac hypertrophy and elucidate the underlying mechanisms in hypertrophic myocytes and rat models through using lentiviral transfection, RNA interference technology, agonists and inhibitors of the key signal pathway and combining multiple molecular biology techniques. Our study will be helpful to provide a potential novel target for clinical prevention and treatment of heart failure.

心肌肥厚是引发心衰的重要因素，预防心肌肥厚是防止心衰发生的重要途径。已有研究表明，PGAM2（磷酸甘油酸变位酶2）通过改变糖酵解能量代谢途径诱导心衰。PGAM2是否参与心肌肥厚的发生及相关机制，未见报道。我们的前期工作发现，在心肌肥厚发生中PGAM2的表达显著增加，沉默其表达能抑制心肌肥厚，表明PGAM2可能是调控心肌肥厚的关键因子。同时发现与PGAM2相互作用并受其调控的热休克蛋白90（HSP90）。已有报道，PPARα和NFκB是的HSP90的下游因子，且参与心脏重塑，由此我们提出“PGAM2通过与HSP90相互作用，调控PPARα和NFκB，参与心肌肥厚”的假说。本研究拟采用心肌肥厚的细胞和大鼠模型，利用慢病毒转染、RNA干扰以及关键信号通路分子的激活剂和拮抗剂，同时结合多种分子生物学手段，力图明确PGAM2在心肌肥厚中的作用及具体机制，为临床科学防控心衰提供一个潜在的新靶点。

心肌肥厚是导致心衰发生的重要因素，抑制心肌肥厚可有效防控心衰发生。本项目的研究表明，PGAM2在心肌肥厚的发生中发挥关键作用。在原代提取的Wistar乳鼠心肌细胞及心肌肥厚大鼠模型中，敲低PGAM2的表达，显著抑制血管紧张素II（Ang II）诱导的心肌肥厚。通过免疫共沉淀结合质谱分析，我们发现HSP90是PGAM2的重要互作蛋白，且二者的主要作用位点在HSP90的中间结构域。通过Duolink PLA及Co-IP技术，我们进一步证实了二者的相互作用。最新研究发现HSP90是心肌肥厚的重要调控因子。我们的结果显示，干扰PGAM2的表达显著抑制HSP90，并显著抑制Ang II诱导的心肌肥厚。但是，在同时敲低PGAM2并过表达HSP90的心肌细胞中，PGAM2敲低对于心肌肥厚的抑制效果被阻断。这些结果说明PGAM2通过HSP90在心肌肥厚中发挥重要调控作用。同时，我们的结果显示PPARα和p65是PGAM2和HSP90的重要下游效应因子，参与心肌肥厚的发生。应用PPARα抑制剂，能够阻断敲低PGAM2对于心肌的保护作用。因此，本项目的重要研究结论是PGAM2通过HSP90及下游的PPAR/p65信号通路调控心肌肥厚。此外，我们的研究还发现敲低PGAM2也能够抑制Ang II所诱导的心肌纤维化。本研究成果拓展了对PGAM2在心肌肥厚中的作用及功能的认识，同时将为临床预防和控制心肌肥厚及心衰提供新的潜在治疗靶点，具有重要的临床意义和价值。