Mukhopadhyay Subhradip, Antalis Toni M, Nguyen Khanh P, Hoofnagle Mark H, Sarkar Rajabrata
Center for Vascular and Inflammatory Diseases.
Department of Surgery, and.
Blood. 2017 Jun 15;129(24):3245-3255. doi: 10.1182/blood-2016-07-727180. Epub 2017 Mar 20.
Deep venous thrombosis (DVT) remains a common and serious cardiovascular problem with both fatal and long-term consequences. The consequences of DVT include the development of postthrombotic syndrome in 25% to 60% of DVT patients. Despite the clinical importance of venous thrombus resolution, the cellular and molecular mediators involved are poorly understood, and currently there is no molecular therapy to accelerate this process. Several lines of evidence suggest that a complex and interrelated array of molecular signaling processes are involved in the inflammatory vascular remodeling associated with the resolution of DVT. Here, we have identified a role for the tumor suppressor gene p53 in regulating venous thrombus resolution. Using the stasis model of venous thrombosis and resolution in mice, we found that genetic deficiency of p53 or pharmacologic inhibition by pifithrin impairs thrombus resolution and is associated with increased fibrosis and altered expression of matrix metalloproteinase-2. The effect of p53 loss was mediated by cells of the myeloid lineage, resulting in enhanced polarization of the cytokine milieu toward an M1-like phenotype. Furthermore, augmentation of p53 activity using the pharmacological agonist of p53, quinacrine, accelerates venous thrombus resolution in a p53-dependent manner, even after establishment of thrombosis. Together, these studies define mechanisms by which p53 regulates thrombus resolution by increasing inflammatory vascular remodeling of venous thrombi in vivo, and the potential therapeutic application of a p53 agonist as a treatment to accelerate this process in patients with DVT.
深静脉血栓形成（DVT）仍然是一个常见且严重的心血管问题，会导致致命和长期后果。DVT的后果包括25%至60%的DVT患者出现血栓后综合征。尽管静脉血栓溶解在临床上很重要，但参与其中的细胞和分子介质却知之甚少，目前尚无分子疗法来加速这一过程。有几条证据表明，一系列复杂且相互关联的分子信号传导过程参与了与DVT溶解相关的炎症性血管重塑。在此，我们确定了肿瘤抑制基因p53在调节静脉血栓溶解中的作用。利用小鼠静脉血栓形成和溶解的淤滞模型，我们发现p53基因缺陷或pifithrin的药理抑制会损害血栓溶解，并与纤维化增加和基质金属蛋白酶-2表达改变有关。p53缺失的影响是由髓系细胞介导的，导致细胞因子环境向M1样表型增强极化。此外，使用p53的药理激动剂奎纳克林增强p53活性，即使在血栓形成后，也能以p53依赖的方式加速静脉血栓溶解。总之，这些研究确定了p53通过增加体内静脉血栓的炎症性血管重塑来调节血栓溶解的机制，以及p53激动剂作为治疗手段加速DVT患者这一过程的潜在治疗应用。
