Background: Sustained inflammation in the heart is sufficient to provoke left ventricular dysfunction and left ventricular remodeling. Although inflammation has been linked to many of the biological changes responsible for adverse left ventricular remodeling, the relationship between inflammation and protein quality control in the heart is not well understood.

Methods and Results: To study the relationship between chronic inflammation and protein quality control, we used a mouse model of dilated cardiomyopathy driven by cardiac restricted overexpression of TNF (tumor necrosis factor; Myh6-sTNF). Myh6-sTNF mice develop protein aggregates containing ubiquitin-tagged proteins within cardiac myocytes related to proteasome dysfunction and impaired autophagy. The 26S proteasome was dysfunctional despite normal function of the core 20S subunit. We found an accumulation of autophagy substrates in Myh6-sTNF mice, which were also seen in tissue from patients with end-stage heart failure. Moreover, there was evidence of impaired autophagosome clearance after chloroquine administration in these mice indicative of impaired autophagic flux. Finally, there was increased mammalian target of rapamycin complex 1 (mTORC1) activation, which has been linked to inhibition of both the proteasome and autophagy.

Conclusions: Myh6-sTNF mice with sustained inflammatory signaling develop proteasome dysfunction and impaired autophagic flux that is associated with enhanced mTORC1 activation.

背景：心脏持续的炎症足以引起左心功能不全和左心室重塑。尽管炎症与导致不良左心室重塑的许多生物学变化有关，但人们对炎症与心脏蛋白质质量控​​制之间的关系尚不甚了解。

方法和结果：为了研究慢性炎症与蛋白质质量控​​制之间的关系，我们使用了由心脏限制性过度表达TNF（肿瘤坏死因子；Myh6- sTNF）驱动的扩张型心肌病小鼠模型。Myh6- sTNF小鼠在与蛋白酶体功能障碍和自噬受损相关的心肌细胞内形成含有泛素标记蛋白的蛋白聚集体。尽管核心20S亚基功能正常，但26S蛋白酶体仍功能异常。我们在Myh6中发现了自噬底物的积累-sTNF小鼠，在末期心力衰竭患者的组织中也可见到。此外，有证据表明在这些小鼠中施用氯喹后自噬体清除能力受损，表明自噬通量受损。最后，雷帕霉素复合物1（mTORC1）激活的哺乳动物靶标增加，这与抑制蛋白酶体和自噬有关。

结论： 具有持续炎症信号的Myh6- sTNF小鼠发展为蛋白酶体功能障碍和自噬通量受损，这与增强的mTORC1活化有关。