PDF(Pubmed)
Abstract：
Pulmonary arterial hypertension (PAH) causes pulmonary vascular remodeling, increasing pulmonary vascular resistance (PVR) and leading to right heart failure and death. Matrix stiffening early in the disease promotes remodeling in pulmonary artery smooth muscle cells (PASMCs), contributing to PAH pathogenesis. Our research identified YAP and TAZ as key drivers of the mechanobiological feedback loop in PASMCs, suggesting targeting them could mitigate remodeling. However, YAP/TAZ are ubiquitously expressed and carry out diverse functions, necessitating a cell-specific approach. Our previous work demonstrated that targeting non-canonical IKB kinase TBK1 reduced YAP/TAZ activation in human lung fibroblasts. Here, we investigate non-canonical IKB kinases TBK1 and IKKε in pulmonary hypertension (PH) and their potential to modulate PASMC pathogenic remodeling by regulating YAP/TAZ. We show that TBK1 and IKKε are activated in PASMCs in a rat PH model. Inflammatory cytokines, elevated in PAH, activate these kinases in human PASMCs. Inhibiting TBK1/IKKε expression/activity significantly reduces PAH-associated PASMC remodeling, with longer-lasting effects on YAP/TAZ than treprostinil, an approved PAH therapy. These results show that non-canonical IKB kinases regulate YAP/TAZ in PASMCs and may offer a novel approach for reducing vascular remodeling in PAH.
摘要：
肺动脉高压(PAH)引起肺血管重构,增加肺血管阻力（PVR）并导致右心衰竭和死亡。疾病早期的基质硬化促进肺动脉平滑肌细胞（PASMC）的重塑，有助于PAH的发病机制。我们的研究确定YAP和TAZ是PASMC机械生物学反馈回路的关键驱动因素，表明靶向它们可以减轻重塑。然而,YAP/TAZ广泛表达并执行多种功能，需要细胞特异性方法。我们先前的工作表明，靶向非规范IKB激酶TBK1降低了人肺成纤维细胞中YAP/TAZ的激活。这里,我们研究了非经典IKB激酶TBK1和IKKε在肺动脉高压（PH）中的作用，以及它们通过调节YAP/TAZ调节PASMC致病性重塑的潜力。我们显示，在大鼠PH模型中，TBK1和IKKε在PASMC中被激活。炎性细胞因子,在PAH中升高，激活人类PASMC中的这些激酶。抑制TBK1/IKKε表达/活性显著降低PAH相关的PASMC重塑,对YAP/TAZ的影响比曲前列环素更持久，批准的PAH疗法。这些结果表明，非经典IKB激酶可调节PASMC中的YAP/TAZ，并可能为减少PAH中的血管重塑提供新方法。
