Milewicz Dianna M, Prakash Siddharth K, Ramirez Francesco
Division of Medical Genetics, Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, Texas 77030; email:
Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
Annu Rev Med. 2017 Jan 14;68:51-67. doi: 10.1146/annurev-med-100415-022956.
Thoracic aortic diseases, including aneurysms and dissections of the thoracic aorta, are a major cause of morbidity and mortality. Risk factors for thoracic aortic disease include increased hemodynamic forces on the ascending aorta, typically due to poorly controlled hypertension, and heritable genetic variants. The altered genes predisposing to thoracic aortic disease either disrupt smooth muscle cell (SMC) contraction or adherence to an impaired extracellular matrix, or decrease canonical transforming growth factor beta (TGF-β) signaling. Paradoxically, TGF-β hyperactivity has been postulated to be the primary driver for the disease. More recently, it has been proposed that the response of aortic SMCs to the hemodynamic load on a structurally defective aorta is the primary driver of thoracic aortic disease, and that TGF-β overactivity in diseased aortas is a secondary, unproductive response to restore tissue function. The engineering of mouse models of inherited aortopathies has identified potential therapeutic agents to prevent thoracic aortic disease.
胸主动脉疾病，包括胸主动脉瘤和夹层，是发病和死亡的主要原因。胸主动脉疾病的危险因素包括升主动脉上血流动力学力增加，通常是由于高血压控制不佳，以及遗传性基因变异。易患胸主动脉疾病的基因改变要么破坏平滑肌细胞（SMC）收缩或与受损细胞外基质的粘附，要么降低经典转化生长因子β（TGF-β）信号传导。矛盾的是，TGF-β过度活跃被认为是该疾病的主要驱动因素。最近，有人提出主动脉SMC对结构缺陷主动脉上血流动力学负荷的反应是胸主动脉疾病的主要驱动因素，而患病主动脉中TGF-β过度活跃是恢复组织功能的次要的、无效的反应。遗传性主动脉病小鼠模型的构建已经确定了预防胸主动脉疾病的潜在治疗药物。
