摘要

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-β1 (TGF-β1) was confirmed by chromatin immunoprecipitation and luciferase assays. Finally, the effects of TGF-β1 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-β1-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-β1 signals are identified as Foxp1 direct target genes, and EC-Foxp1 deletion upregulates TGF-β1 signals to promote myofibroblast formation through fibroblast proliferation and transformation, resulting in severe cardiac fibrosis. Moreover, EC-Foxp1 deletion enhances TGF-β1-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-β1 signals through pharmacological inhibition and RGD-peptide magnetic nanoparticle target delivery of TGF-β1-siRNA to ECs.
CONCLUSIONS:EC-Foxp1 regulates the TGF-β1-endothelin-1 pathway to control pathological cardiac fibrosis and hypertrophy, resulting in cardiac dysfunction. Therefore, targeting the EC-Foxp1-TGF-β1-endothelin-1 pathway might provide a future novel therapy for heart failure.

译文

背景: 病理性心肌纤维化和肥大是左心室重构的共同特征，常进展为心力衰竭。内皮细胞 (ECs) 中的叉头框转录因子 P1 (Foxp1) 已被证明在心脏发育中发挥重要作用。然而，EC-Foxp1 对病理性心脏重构的影响尚未明确。本研究旨在确定 EC-Foxp1 在病理性心脏重构中的作用及其机制。
方法: 产生 Foxp1 EC 特异性功能丧失和功能增益小鼠, 并使用血管紧张素 ⅱ 输注或主动脉横缩手术小鼠模型来研究心脏重构机制。通过染色质免疫沉淀和荧光素酶试验证实了 Foxp1 下游靶基因转化生长因子-β 1 (TGF-β 1)。最后，通过药理抑制进一步证实了 TGF-β 1 阻断对 EC-Foxp1 缺失介导的促纤维化和促肥厚表型变化的影响, 更具体地说，通过 RGD-肽磁性纳米颗粒靶向递送 TGF-β 1-siRNA 到 ECs。
结果: 在血管紧张素 ⅱ 诱导的心脏重构过程中，Foxp1 在心脏 ECs 中的表达显著下调。EC-Foxp1 缺失导致严重的心脏重构，包括更多的心脏纤维化和肌成纤维细胞形成以及细胞外基质蛋白的产生, 以及失代偿性心肌肥厚和血管紧张素 II 输注或主动脉横缩窄手术导致的心脏功能障碍的进一步恶化。相反，EC-Foxp1 功能的增加可以防止病理性心脏重构并改善心脏功能障碍。TGF-β 1 信号被鉴定为 Foxp1 直接靶基因，EC-Foxp1 缺失上调 TGF-β 1 信号，通过成纤维细胞的增殖和转化促进肌成纤维细胞的形成，导致严重的心脏纤维化。此外，EC-Foxp1 缺失增强了 TGF-β 1 促进的 endothelin-1 表达，从而显著增加心肌细胞大小并重新激活心脏胎儿基因，导致病理性心肌肥大。相应地, 这些 EC-Foxp1 缺失介导的前纤维化和前肥厚表型变化和心脏功能障碍通过药物抑制和 RGD-肽磁性纳米颗粒靶向递送 TGF-β 1-siRNA 来阻断 TGF-β 1 信号。致 ECs。
结论: EC-Foxp1 通过调控 TGF-β 1-endothelin-1 通路来控制病理性心肌纤维化和肥大，从而导致心脏功能障碍。因此，靶向 EC-Foxp1-TGF-β 1-endothelin-1 通路可能为心力衰竭提供未来的新疗法。