PDF(Pubmed)
Abstract：
Rationale: TGFβ signaling pathway controls tissue fibrotic remodeling, a hallmark in many diseases leading to organ injury and failure. In this study, we address the role of Apilimod, a pharmacological inhibitor of the lipid kinase PIKfyve, in the regulation of cardiac pathological fibrotic remodeling and TGFβ signaling pathway. Methods: The effects of Apilimod treatment on myocardial fibrosis, hypertrophy and cardiac function were assessed in vivo in a mouse model of pressure overload-induced heart failure. Primary cardiac fibroblasts and HeLa cells treated with Apilimod as well as genetic mutation of PIKfyve in mouse embryonic fibroblasts were used as cell models. Results: When administered in vivo, Apilimod reduced myocardial interstitial fibrosis development and prevented left ventricular dysfunction. In vitro, Apilimod controlled TGFβ-dependent activation of primary murine cardiac fibroblasts. Mechanistically, both Apilimod and genetic mutation of PIKfyve induced TGFβ receptor blockade in intracellular vesicles, negatively modulating its downstream signaling pathway and ultimately dampening TGFβ response. Conclusions: Altogether, our findings propose a novel function for PIKfyve in the control of myocardial fibrotic remodeling and the TGFβ signaling pathway, therefore opening the way to new therapeutic perspectives to prevent adverse fibrotic remodeling using Apilimod treatment.
摘要：
原理：TGFβ信号通路控制组织纤维化重塑，许多导致器官损伤和衰竭的疾病的标志。在这项研究中,我们讨论阿吡莫德的作用，脂质激酶PIKfyve的药理学抑制剂，在心脏病理性纤维化重塑和TGFβ信号通路的调控中。方法：阿吡莫德治疗对心肌纤维化的影响，在压力超负荷诱导的心力衰竭小鼠模型中体内评估肥大和心功能.用Apilimod处理的原代心脏成纤维细胞和HeLa细胞以及小鼠胚胎成纤维细胞中PIKfyve的基因突变被用作细胞模型。结果：体内给药时，阿吡莫德减少心肌间质纤维化发展并预防左心室功能障碍。体外，阿吡莫德控制原代鼠心脏成纤维细胞的TGFβ依赖性活化。机械上,Apilimod和PIKfyve的基因突变均可诱导细胞内囊泡中的TGFβ受体阻断，负调节其下游信号通路并最终抑制TGFβ反应。结论：总之，我们的发现提出了PIKfyve在控制心肌纤维化重塑和TGFβ信号通路中的新功能，因此，为使用阿吡莫德治疗预防不良纤维化重塑的新治疗观点开辟了道路。
