Department of Bioengineering, Rice University, 6500 Main St, Houston, TX 77030, United States.
Acta Biomater. 2021 Jun;127:159-168. doi: 10.1016/j.actbio.2021.03.075. Epub 2021 Apr 6.
Mitral valve disease is a major cause of cardiovascular morbidity throughout the world. Many different mitral valve pathologies feature fibrotic remodeling, often accompanied by an inflammatory state. Mitral valve fibrosis is mediated by valvular interstitial cells (VICs), which reside in the valve leaflets and often differentiate into myofibroblast-like cells during disease conditions. In this study, we investigated the effects of tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β) on mitral VICs, since these pro-inflammatory cytokines have been shown to exert pleiotropic effects on various cell types in other fibrotic disorders. Using biomimetic three-dimensional culture systems, we demonstrated that TNF-α and IL-1β suppress myofibroblast differentiation in mitral VICs, as evidenced by gene and protein expression of alpha smooth muscle actin and smooth muscle 22 alpha. Addition of TNF-α and IL-1β also inhibited mitral VIC-mediated contraction of collagen gels. Furthermore, inhibition of NF-κB, which is downstream of TNF-α and IL-1β, reversed these effects. These results reveal targetable pathways for potential development of pharmaceutical treatments for alleviating fibrosis during mitral valve disease. STATEMENT OF SIGNIFICANCE: Mitral valve disease is a common cardiovascular condition that is often accompanied by fibrotic tissue remodeling. Valvular interstitial cells (VICs), the fibroblast-like cells that reside in heart valve leaflets, are thought to drive fibrosis during valve disease by differentiating into activated myofibroblasts. However, the signaling pathways that regulate this process in the mitral valve are not fully understood. In the present study, we cultured mitral VICs in collagen and poly(ethylene glycol) scaffolds designed to mimic the heart valve microenvironment and treated the cell-seeded scaffolds with cytokines. Using these 3D culture models, we found that the pro-inflammatory cytokines TNF-α and IL-1β downregulate myofibroblast and fibrosis markers in mitral VICs via the canonical NF-κB signaling pathway.
二尖瓣疾病是全球心血管发病率的主要原因。许多不同的二尖瓣病变都具有纤维性重塑的特征，通常伴有炎症状态。二尖瓣纤维化是由瓣叶中的瓣膜间质细胞（VIC）介导的，VIC 在疾病状态下通常分化为肌成纤维细胞样细胞。在这项研究中，我们研究了肿瘤坏死因子-α（TNF-α）和白细胞介素 1β（IL-1β）对二尖瓣 VIC 的影响，因为这些促炎细胞因子已被证明对其他纤维化疾病中的各种细胞类型具有多效作用。使用仿生三维培养系统，我们证明 TNF-α 和 IL-1β 抑制二尖瓣 VIC 中的肌成纤维细胞分化，这表现在α平滑肌肌动蛋白和平滑肌 22α 的基因和蛋白表达上。添加 TNF-α 和 IL-1β 也抑制了二尖瓣 VIC 介导的胶原凝胶收缩。此外，抑制 TNF-α 和 IL-1β 的下游 NF-κB 逆转了这些作用。这些结果揭示了可靶向的途径，为开发潜在的药物治疗方法缓解二尖瓣疾病中的纤维化提供了依据。
二尖瓣疾病是一种常见的心血管疾病，常伴有纤维组织重塑。位于心脏瓣膜小叶中的瓣膜间质细胞（VIC）被认为通过分化为激活的肌成纤维细胞来驱动瓣膜疾病中的纤维化。然而，调节二尖瓣中这一过程的信号通路尚不完全清楚。在本研究中，我们在胶原蛋白和聚乙二醇支架中培养二尖瓣 VIC，这些支架旨在模拟心脏瓣膜微环境，并在细胞接种的支架上用细胞因子处理。使用这些 3D 培养模型，我们发现促炎细胞因子 TNF-α 和 IL-1β 通过经典的 NF-κB 信号通路下调二尖瓣 VIC 中的肌成纤维细胞和纤维化标志物。
