Disconnect between Fibrotic Response and Right Ventricular Dysfunction
Disconnect between Fibrotic Response and Right Ventricular Dysfunction
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DOI：
10.1164/rccm.201809-1737oc
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发表时间：
2019-06-15
影响因子：
24.7
通讯作者：
Kwapiszewska, Grazyna
中科院分区：
文献类型：
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作者：
Crnkovic, Slaven;Egemnazarov, Bakytbek;Kwapiszewska, Grazyna
基本原理：右心室 (RV) 重塑和纤维化可能导致肺动脉高压患者的 RV 功能障碍和不良生存。目的：研究 RV 纤维化调节和伴随的细胞变化对 RV 功能的影响。方法：评估肺动脉高压患者的 RV、小鼠肺动脉环带以及大鼠野百合碱和 Sugen5416/缺氧模型中纤维化标志物的表达。对半乳糖凝集素 3 敲除或抑制剂治疗的小鼠进行侵入性血流动力学和超声心动图评估。测量和主要结果：已形成的纤维化的特征是半乳糖凝集素 3 的显着表达和增殖的 RV 成纤维细胞数量增加。 Galectin-3 遗传和药理学抑制或吡非尼酮抗纤维化治疗可显着减少肺动脉结扎模型中的 RV 纤维化进展，但不会改善 RV 功能参数。 RV 纤维化区域充满了共表达波形蛋白和 PDGFR α（血小板衍生生长因子受体-α）的间充质细胞，但通常缺乏 α SMA（α-平滑肌肌动蛋白）阳性。特发性肺动脉高压患者的血清半乳糖凝集素-3水平升高，但与心功能无关。肺部中未观察到半乳糖凝集素 3 表达的变化。结论：我们确定肺外半乳糖凝集素 3 是通过表达 PDGFR α/波形蛋白的心脏成纤维细胞扩张而驱动肺动脉高压中 RV 纤维化的重要介质。然而，有效针对纤维化的干预措施对右心室功能缺乏显着的有益作用。
Rationale: Remodeling and fibrosis of the right ventricle (RV) may cause RV dysfunction and poor survival in patients with pulmonary hypertension.Objectives: To investigate the consequences of RV fibrosis modulation and the accompanying cellular changes on RV function.Methods: Expression of fibrotic markers was assessed in the RV of patients with pulmonary hypertension, the murine pulmonary artery banding, and rat monocrotaline and Sugen5416/hypoxia models. Invasive hemodynamic and echocardiographic assessment was performed on galectin-3 knockout or inhibitor-treated mice.Measurements and Main Results: Established fibrosis was characterized by marked expression of galectin-3 and an enhanced number of proliferating RV fibroblasts. Galectin-3 genetic and pharmacologic inhibition or antifibrotic treatment with pirfenidone significantly diminished RV fibrosis progression in the pulmonary artery banding model, without improving RV functional parameters. RV fibrotic regions were populated with mesenchymal cells coexpressing vimentin and PDGFR alpha (platelet-derived growth factor receptor-alpha), but generally lacked alpha SMA (alpha-smooth muscle actin) positivity. Serum levels of galectin-3 were increased in patients with idiopathic pulmonary arterial hypertension but did not correlate with cardiac function. No changes of galectin-3 expression were observed in the lungs.Conclusions: We identified extrapulmonary galectin-3 as an important mediator that drives RV fibrosis in pulmonary hypertension through the expansion of PDGFR alpha/vimentinexpressing cardiac fibroblasts. However, interventions effectively targeting fibrosis lack significant beneficial effects on RV function.