RAGE-mediated extracellular matrix proteins accumulation exacerbates HySu-induced pulmonary hypertension
RAGE-mediated extracellular matrix proteins accumulation exacerbates HySu-induced pulmonary hypertension
复制标题
RAGE介导的细胞外基质蛋白积累加剧了HySu诱导的肺动脉高压
DOI：
10.1093/cvr/cvx051
复制
发表时间：
2017-05-01
影响因子：
10.8
通讯作者：
Lu, Ankang
中科院分区：
文献类型：
--
作者：
Jia, Daile;He, Yuhu;Lu, Ankang
目标
细胞外基质 (ECM) 蛋白的积累会导致肺动脉高压 (PAH) 的进展，这是一种罕见且致命的心血管疾病，由高肺动脉压定义，无论是原发性、特发性还是其他原因继发性。晚期糖基化终末产物 (RAGE) 受体在肺部持续表达，在 ECM 沉积中发挥重要作用。尽管如此，RAGE 介导肺动脉中 ECM 沉积/形成的机制及其在 PAH 进展中的作用仍不清楚。
方法和结果
在缺氧条件下，人和小鼠肺动脉平滑肌细胞 (PASMC) 中 RAGE 及其激活配体 S100/钙粒蛋白和高迁移率族蛋白 1 (HMGB1) 的表达均增加，并且在缺氧加 SU5416 (HySu) 诱导的小鼠 PAH 中，肺动脉中的表达也显着上调。在 HySu 诱导的 PAH 小鼠模型中，RAGE 缺失可减轻肺动脉压并抑制肺动脉中细胞外基质的积累。此外，用人 PASMC 中的中和抗体阻断 RAGE 活性，或暴露于缺氧的小鼠 PASMC 中 RAGE 缺陷，可以通过减少 TGF-β1 表达来抑制纤维化蛋白的表达。缺陷小鼠 PASMC 中的 RAGE 重建可通过 ERK1/2 和 p38 MAPK 通路激活恢复缺氧刺激的 TGF-β1 产生，并随后增加 ECM 蛋白表达。有趣的是，HMGB1 作用于 RAGE，而不是 Toll 样受体 4 (TLR4)，诱导 PASMC 中 ECM 沉积。最后，在特发性 PAH 患者和 HySu 诱导的 PAH 小鼠中，血清中可溶性 RAGE (sRAGE) 水平与对照组相比显着升高。
结论
RAGE 的激活通过增加肺动脉中的 ECM 沉积促进缺氧诱导的肺动脉高压的发展。我们的结果表明，sRAGE 可能是 PAH 诊断和疾病严重程度的潜在生物标志物，并且 RAGE 可能是 PAH 治疗的有希望的靶点。
Aims
Extracellular matrix (ECM) proteins accumulation contributes to the progression of pulmonary arterial hypertension (PAH), a rare and fatal cardiovascular condition defined by high pulmonary arterial pressure, whether primary, idiopathic, or secondary to other causes. The receptor for advanced glycation end products (RAGE) is constitutively expressed in the lungs and plays an important role in ECM deposition. Nonetheless, the mechanisms by which RAGE mediates ECM deposition/formation in pulmonary arteries and its roles in PAH progression remain unclear.
Methods and results
Expression of RAGE and its activating ligands, S100/calgranulins and high mobility group box 1 (HMGB1), were increased in both human and mouse pulmonary arterial smooth muscle cells (PASMCs) under hypoxic conditions and were also strikingly upregulated in pulmonary arteries in hypoxia plus SU5416 (HySu)-induced PAH in mice. RAGE deletion alleviated pulmonary arterial pressure and restrained extracellular matrix accumulation in pulmonary arteries in HySu-induced PAH murine model. Moreover, blocking RAGE activity with a neutralizing antibody in human PASMCs, or RAGE deficiency in mouse PASMCs exposed to hypoxia, suppressed the expression of fibrotic proteins by reducing TGF-β1 expression. RAGE reconstitution in deficient mouse PASMCs restored hypoxia-stimulated TGF-β1 production via ERK1/2 and p38 MAPK pathway activation and subsequently increased ECM protein expression. Interestingly, HMGB1 acting on RAGE, not toll-like receptor 4 (TLR4), induced ECM deposition in PASMCs. Finally, in both idiopathic PAH patients and HySu-induced PAH mice, soluble RAGE (sRAGE) levels in serum were significantly elevated compared to those in controls.
Conclusions
Activation of RAGE facilitates the development of hypoxia-induced pulmonary hypertension by increase of ECM deposition in pulmonary arteries. Our results indicate that sRAGE may be a potential biomarker for PAH diagnosis and disease severity, and that RAGE may be a promising target for PAH treatment.