Tgfβ1-Cthrc1 Signaling Plays an Important Role in the Short-Term Reparative Response to Heart Valve Endothelial Injury.
Tgfβ1-Cthrc1 Signaling Plays an Important Role in the Short-Term Reparative Response to Heart Valve Endothelial Injury.
复制标题
DOI：
10.1161/atvbaha.121.316450
复制
发表时间：
2021-12
期刊：
影响因子：
--
通讯作者：
Lincoln J
中科院分区：
文献类型：
--
作者：
Nordquist EM;Dutta P;Kodigepalli KM;Mattern C;McDermott MR;Trask AJ;LaHaye S;Lindner V;Lincoln J
主动脉瓣疾病是一种常见的全球健康负担，治疗选择有限。研究表明，瓣膜内皮对结构-功能关系至关重要，疾病与其功能障碍、损伤或损伤有关。因此，维持健康内皮或修复受损内皮细胞的治疗目标可能有希望。在本研究中，我们利用心脏瓣膜内皮细胞损伤的外科小鼠模型，在分子和细胞水平上研究对损伤的短期反应。目的是确定天然心脏瓣膜是否表现出修复反应，并确定这一过程的机制。通过将导丝沿年轻（3个月）和老龄（16-18个月）野生型小鼠的颈动脉插入，诱发轻度主动脉瓣内皮损伤和功能丧失。在损伤后6小时、48小时和4周检查短期细胞反应，而在48小时后通过RNA测序确定分子谱。在内皮损伤后48小时内，年轻野生型小鼠恢复内皮屏障功能，并增加细胞增殖，上调TGFβ1和糖蛋白胶原蛋白三重抑制重复序列1（Cthrc 1）。有趣的是，在已知潜在内皮功能障碍的衰老小鼠中没有观察到这种对损伤的有益反应。本研究的数据表明，健康瓣膜有能力对轻度内皮损伤做出反应，短期内，通过急性激活Tgfβ1-Cthrc 1信号轴和细胞增殖，对恢复内皮屏障功能具有有益作用。
Aortic valve disease is a common worldwide health burden with limited treatment options. Studies have shown that the valve endothelium is critical for structure-function relationships, and disease is associated with its dysfunction, damage or injury. Therefore, therapeutic targets to maintain a healthy endothelium, or repair damaged endothelial cells could hold promise. In this current study, we utilize a surgical mouse model of heart valve endothelial cell injury to study the short-term response to injury at molecular and cellular levels. The goal is to determine if the native heart valve exhibits a reparative response, and identify the mechanisms underlying this process. Mild aortic valve endothelial injury and abrogated function was evoked by inserting a guidewire down the carotid artery of young (3 months) and aging (16–18 months) wildtype mice. Short-term cellular responses were examined at 6 hours, 48 hours, and 4 weeks following injury, while molecular profiles were determined after 48 hours by RNA-sequencing. Within 48 hours following endothelial injury, young wildtype mice restore endothelial barrier function in association with increased cell proliferation, and upregulation of Tgfβ1 and the glycoprotein, Collagen Triple Helix Repeat Containing 1 (Cthrc1). Interestingly, this beneficial response to injury was not observed in aging mice with known underlying endothelial dysfunction. Data from this study suggests that the healthy valve has the capacity to respond to mild endothelial injury, which short-term, has beneficial effects on restoring endothelial barrier function through acute activation of the Tgfβ1-Cthrc1 signaling axis and cell proliferation.