Therapeutics Targeting Drivers of Thoracic Aortic Aneurysms and Acute Aortic Dissections: Insights from Predisposing Genes and Mouse Models.
Therapeutics Targeting Drivers of Thoracic Aortic Aneurysms and Acute Aortic Dissections: Insights from Predisposing Genes and Mouse Models.
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DOI：
10.1146/annurev-med-100415-022956
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发表时间：
2017-01-14
影响因子：
10.5
通讯作者：
Ramirez F
中科院分区：
文献类型：
--
作者：
Milewicz DM;Prakash SK;Ramirez F
胸主动脉疾病，包括胸主动脉的动脉瘤和夹层，是发病率和死亡率的主要原因。胸主动脉疾病的危险因素包括升主动脉血流动力学力增加，通常是由于控制不良的高血压和遗传性遗传变异。易患胸主动脉疾病的基因改变会破坏平滑肌细胞（SMC）收缩或粘附受损的细胞外基质，或降低典型的转化生长因子β（TGF-β）信号传导。巧合的是，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的血流动力学负荷的反应是胸主动脉疾病的主要驱动因素，并且患病动脉中的TGF-β过度活性是恢复组织功能的次要的非生产性反应。遗传性胸主动脉病变小鼠模型的工程化已经确定了预防胸主动脉疾病的潜在治疗剂。
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 over-activity 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.