Department of Cardiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijiner Road, Shanghai 200025, China.
Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 yueyang Road, Shanghai 200031, China.
Cardiovasc Res. 2017 May 1;113(6):586-597. doi: 10.1093/cvr/cvx051.
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.
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.
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.
细胞外基质（ECM）蛋白的积累导致肺动脉高压（PAH）的进展，PAH 是一种罕见且致命的心血管疾病，其特征是肺动脉压升高，无论是原发性、特发性还是由其他原因引起的继发性。晚期糖基化终产物受体（RAGE）在肺部持续表达，在 ECM 沉积中发挥重要作用。然而，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。
在缺氧条件下，人及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 B1（HMGB1）的表达增加，并且在缺氧加 SU5416（HySu）诱导的小鼠 PAH 中肺动脉中也显著上调。RAGE 缺失减轻了 HySu 诱导的 PAH 小鼠模型中的肺动脉压力并抑制了肺动脉中 ECM 的积累。此外，在人 PASMC 中用中和抗体阻断 RAGE 活性，或在缺氧的鼠 PASMC 中缺乏 RAGE，通过减少 TGF-β1 的表达来抑制纤维化蛋白的表达。在缺乏 RAGE 的鼠 PASMC 中重建 RAGE 恢复了缺氧刺激的 TGF-β1 产生，通过 ERK1/2 和 p38 MAPK 通路的激活，随后增加 ECM 蛋白的表达。有趣的是，HMGB1 通过 RAGE 而不是 Toll 样受体 4（TLR4）作用于 PASMC 引起 ECM 沉积。最后，在特发性 PAH 患者和 HySu 诱导的 PAH 小鼠中，与对照组相比，血清中可溶性 RAGE（sRAGE）水平显著升高。
RAGE 的激活通过增加肺动脉中 ECM 的沉积促进了缺氧诱导的肺动脉高压的发展。我们的研究结果表明，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。
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