Division of Molecular Cardiology, Department of Medicine, College of Medicine, Texas A&M Health Science Center, College Station, TX 77840, USA.
Free Radic Biol Med. 2011 Jan 1;50(1):206-15. doi: 10.1016/j.freeradbiomed.2010.10.711. Epub 2010 Nov 1.
Myocardial remodeling denotes a chronic pathological condition of dysfunctional myocardium that occurs in cardiac hypertrophy (CH) and heart failure (HF). Reactive oxygen species (ROS) are major initiators of excessive collagen and fibronectin deposition in cardiac fibrosis. Increased production of ROS and nuclear factor κB (NF-κB) activation provide a strong link between oxidative stress and extracellular matrix (ECM) remodeling in cardiac hypertrophy. The protective inhibitory actions of pyrrolidine dithiocarbamate (PDTC), a pharmacological inhibitor of NF-κB and a potent antioxidant, make this a good agent to evaluate the role of inhibition of NF-κB and prevention of excessive ECM deposition in maladaptive cardiac remodeling during HF. In this report, we used a transgenic mouse model (Myo-Tg) that has cardiac-specific overexpression of myotrophin. This overexpression of myotrophin in the Myo-Tg model directs ECM deposition and increased NF-κB activity, which result in CH and ultimately HF. Using the Myo-Tg model, our data showed upregulation of profibrotic genes (including collagen types I and III, connective tissue growth factor, and fibronectin) in Myo-Tg mice, compared to wild-type mice, during the progression of CH. Pharmacological inhibition of NF-κB by PDTC in the Myo-Tg mice resulted in a significant reduction in cardiac mass, NF-κB activity, and profibrotic gene expression and improved cardiac function. To the best of our knowledge, this is the first report of ECM regulation by inhibition of NF-κB activation by PDTC. The study highlights the importance of the NF-κB signaling pathway and therapeutic benefits of PDTC treatment in cardiac remodeling.
心肌重构是指心肌功能障碍的一种慢性病理状态，发生于心脏肥大（CH）和心力衰竭（HF）中。活性氧（ROS）是心脏纤维化中胶原和纤维连接蛋白过度沉积的主要启动子。ROS 产生增加和核因子κB（NF-κB）激活为氧化应激与心脏肥大中细胞外基质（ECM）重构之间提供了紧密联系。吡咯烷二硫代氨基甲酸盐（PDTC）作为 NF-κB 的药理学抑制剂和有效的抗氧化剂，具有抑制 NF-κB 作用和预防 ECM 过度沉积的保护抑制作用，使其成为评估 HF 期间抑制 NF-κB 和预防适应性心脏重构中 ECM 过度沉积作用的良好药物。在本报告中，我们使用了一种心脏特异性过表达肌萎缩蛋白的转基因小鼠模型（Myo-Tg）。在 Myo-Tg 模型中，肌萎缩蛋白的过表达导致 ECM 沉积和 NF-κB 活性增加，从而导致 CH 并最终导致 HF。使用 Myo-Tg 模型，与野生型小鼠相比，我们的数据显示在 CH 进展过程中 Myo-Tg 小鼠的促纤维化基因（包括胶原 I 和 III 型、结缔组织生长因子和纤维连接蛋白）表达上调。PDTC 抑制 NF-κB 可使 Myo-Tg 小鼠的心脏质量、NF-κB 活性和促纤维化基因表达显著减少，并改善心脏功能。据我们所知，这是首例通过 PDTC 抑制 NF-κB 激活来调节 ECM 的报道。该研究强调了 NF-κB 信号通路的重要性以及 PDTC 治疗在心脏重构中的治疗益处。
