Halliday Stephen J, Matthews Daniel T, Talati Megha H, Austin Eric D, Su Yan R, Absi Tarek S, Fortune Niki L, Gailani David, Matafonov Anton, West James D, Hemnes Anna R
Division of Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin Madison, Madison, USA.
Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, USA.
JRSM Cardiovasc Dis. 2020 Feb 13;9:2048004020906994. doi: 10.1177/2048004020906994. eCollection 2020 Jan-Dec.
Chronic thromboembolic pulmonary hypertension is characterized by incomplete thrombus resolution following acute pulmonary embolism, leading to pulmonary hypertension and right ventricular dysfunction. Conditions such as thrombophilias, dysfibrinogenemias, and inflammatory states have been associated with chronic thromboembolic pulmonary hypertension, but molecular mechanisms underlying this disease are poorly understood. We sought to characterize the molecular and functional features associated with chronic thromboembolic pulmonary hypertension using a multifaceted approach.
We utilized functional assays to compare clot lysis times between chronic thromboembolic pulmonary hypertension patients and multiple controls. We then performed immunohistochemical characterization of tissue from chronic thromboembolic pulmonary hypertension, pulmonary arterial hypertension, and healthy controls, and examined RNA expression patterns of cultured lymphocytes and pulmonary arterial specimens. We then confirmed RNA expression changes using immunohistochemistry, immunofluorescence, and Western blotting in pulmonary arterial tissue.
Clot lysis times in chronic thromboembolic pulmonary hypertension patients are similar to multiple controls. Chronic thromboembolic pulmonary hypertension endarterectomized tissue has reduced expression of both smooth muscle and endothelial cell markers. RNA expression profiles in pulmonary arteries and peripheral blood lymphocytes identified differences in RNA transcript levels related to inflammation and growth factor signaling, which we confirmed using immunohistochemistry. Gene expression data also suggested significant alterations in metabolic pathways, and immunofluorescence and Western blot experiments confirmed that unglycosylated CD36 and adiponectin expression were increased in chronic thromboembolic pulmonary hypertension versus controls.
Our data do not support impaired clot lysis underlying chronic thromboembolic pulmonary hypertension, but did demonstrate distinct molecular patterns present both in peripheral blood and in pathologic specimens of chronic thromboembolic pulmonary hypertension patients suggesting that altered metabolism may play a role in chronic thromboembolic pulmonary hypertension pathogenesis.
慢性血栓栓塞性肺动脉高压的特征是急性肺栓塞后血栓未完全溶解，导致肺动脉高压和右心室功能障碍。血栓形成倾向、纤维蛋白原异常血症和炎症状态等情况与慢性血栓栓塞性肺动脉高压有关，但该疾病的分子机制尚不清楚。我们试图采用多方面的方法来描述与慢性血栓栓塞性肺动脉高压相关的分子和功能特征。
我们利用功能试验比较慢性血栓栓塞性肺动脉高压患者与多个对照组之间的凝块溶解时间。然后，我们对慢性血栓栓塞性肺动脉高压、肺动脉高压和健康对照的组织进行免疫组织化学特征分析，并检查培养的淋巴细胞和肺动脉标本的RNA表达模式。然后，我们在肺动脉组织中使用免疫组织化学、免疫荧光和蛋白质印迹法确认RNA表达变化。
慢性血栓栓塞性肺动脉高压患者的凝块溶解时间与多个对照组相似。慢性血栓栓塞性肺动脉高压内膜剥脱组织中平滑肌和内皮细胞标志物的表达均降低。肺动脉和外周血淋巴细胞中的RNA表达谱确定了与炎症和生长因子信号传导相关的RNA转录水平差异，我们通过免疫组织化学证实了这一点。基因表达数据还表明代谢途径有显著改变，免疫荧光和蛋白质印迹实验证实，与对照组相比，慢性血栓栓塞性肺动脉高压中未糖基化的CD36和脂联素表达增加。
我们的数据不支持慢性血栓栓塞性肺动脉高压存在凝块溶解受损，但确实证明了慢性血栓栓塞性肺动脉高压患者外周血和病理标本中存在独特的分子模式，这表明代谢改变可能在慢性血栓栓塞性肺动脉高压的发病机制中起作用。
