Endothelial Forkhead Box Transcription Factor P1 Regulates Pathological Cardiac Remodeling Through Transforming Growth Factor-β1-Endothelin-1 Signal Pathway
Endothelial Forkhead Box Transcription Factor P1 Regulates Pathological Cardiac Remodeling Through Transforming Growth Factor-β1-Endothelin-1 Signal Pathway
复制标题
内皮叉头盒转录因子 P1 通过转化生长因子-β 1-内皮素-1 信号通路调节病理性心脏重塑
DOI：
10.1161/circulationaha.119.039767
复制
发表时间：
2019-08-20
期刊：
影响因子：
37.8
通讯作者：
Zhang, Yuzhen
中科院分区：
文献类型：
--
作者：
Liu, Jie;Zhuang, Tao;Zhang, Yuzhen
背景：病理性心肌纤维化和肥厚是左室重构的共同特征，常进展为心力衰竭。叉头盒转录因子P1（Foxp 1）在内皮细胞（ECs）已被证明在心脏发育中发挥重要作用。然而，EC-Foxp 1对病理性心脏重构的影响尚未得到很好的阐明。本研究旨在探讨EC-Foxp 1在病理性心脏重构中的作用及其机制。研究方法：制备Foxp 1 EC特异性功能丧失和功能获得小鼠，并使用血管紧张素II输注或横向主动脉缩窄手术小鼠模型来研究心脏重塑机制。通过染色质免疫沉淀和荧光素酶测定证实了Foxp 1下游靶基因转化生长因子-β 1（TGF-β 1）。最后，TGF-β 1阻断对EC-Foxp 1缺失介导的促纤维化和促肥大表型变化的影响通过药理学抑制进一步证实，更具体地说，通过将TGF-β 1-siRNA靶向递送至EC的RGD肽磁性纳米颗粒。结果：血管紧张素II诱导的心脏重构过程中，Foxp 1的表达显著下调。EC-Foxp 1缺失导致严重的心脏重构，包括更多的心脏纤维化伴肌成纤维细胞形成和细胞外基质蛋白产生，以及失代偿性心脏肥大和血管紧张素II输注或横主动脉缩窄术时心功能不全的进一步加重。相比之下，EC-Foxp 1功能的获得可防止病理性心脏重塑并改善心功能障碍。TGF-β 1信号被鉴定为Foxp 1直接靶基因，EC-Foxp 1缺失上调TGF-β 1信号，通过成纤维细胞增殖和转化促进肌成纤维细胞形成，导致严重的心脏纤维化。此外，EC-Foxp 1缺失增强了TGF-β 1促进的内皮素-1表达，这显著增加了心肌细胞的大小并重新激活心脏胎儿基因，导致病理性心脏肥大。相应地，这些EC-Foxp 1缺失介导的促纤维化和促肥大表型变化和心功能障碍通过药理学抑制和RGD-肽磁性纳米颗粒靶向递送TGF-β 1-siRNA至EC阻断TGF-β 1信号而正常化。结论：EC-Foxp 1通过调节TGF-β 1-内皮素-1通路来控制病理性心脏纤维化和肥大，从而导致心脏功能障碍。因此，靶向EC-Foxp 1-TGF-β 1-内皮素-1通路可能为心力衰竭提供未来的新疗法。
Background: Pathological cardiac fibrosis and hypertrophy, the common features of left ventricular remodeling, often progress to heart failure. Forkhead box transcription factor P1 (Foxp1) in endothelial cells (ECs) has been shown to play an important role in heart development. However, the effect of EC-Foxp1 on pathological cardiac remodeling has not been well clarified. This study aims to determine the role of EC-Foxp1 in pathological cardiac remodeling and the underlying mechanisms. Methods: Foxp1 EC-specific loss-of-function and gain-of-function mice were generated, and an angiotensin II infusion or a transverse aortic constriction operation mouse model was used to study the cardiac remodeling mechanisms. Foxp1 downstream target gene transforming growth factor-beta 1 (TGF-beta 1) was confirmed by chromatin immunoprecipitation and luciferase assays. Finally, the effects of TGF-beta 1 blockade on EC-Foxp1 deletion-mediated profibrotic and prohypertrophic phenotypic changes were further confirmed by pharmacological inhibition, more specifically by RGD-peptide magnetic nanoparticle target delivery of TGF-beta 1-siRNA to ECs. Results: Foxp1 expression is significantly downregulated in cardiac ECs during angiotensin II-induced cardiac remodeling. EC-Foxp1 deletion results in severe cardiac remodeling, including more cardiac fibrosis with myofibroblast formation and extracellular matrix protein production, as well as decompensated cardiac hypertrophy and further exacerbation of cardiac dysfunction on angiotensin II infusion or transverse aortic constriction operation. In contrast, EC-Foxp1 gain of function protects against pathological cardiac remodeling and improves cardiac dysfunction. TGF-beta 1 signals are identified as Foxp1 direct target genes, and EC-Foxp1 deletion upregulates TGF-beta 1 signals to promote myofibroblast formation through fibroblast proliferation and transformation, resulting in severe cardiac fibrosis. Moreover, EC-Foxp1 deletion enhances TGF-beta 1-promoted endothelin-1 expression, which significantly increases cardiomyocyte size and reactivates cardiac fetal genes, leading to pathological cardiac hypertrophy. Correspondingly, these EC-Foxp1 deletion-mediated profibrotic and prohypertrophic phenotypic changes and cardiac dysfunction are normalized by the blockade of TGF-beta 1 signals through pharmacological inhibition and RGD-peptide magnetic nanoparticle target delivery of TGF-beta 1-siRNA to ECs. Conclusions: EC-Foxp1 regulates the TGF-beta 1-endothelin-1 pathway to control pathological cardiac fibrosis and hypertrophy, resulting in cardiac dysfunction. Therefore, targeting the EC-Foxp1-TGF-beta 1-endothelin-1 pathway might provide a future novel therapy for heart failure.