EP3 receptor deficiency attenuates pulmonary hypertension through suppression of Rho/TGF-β1 signaling
EP3 receptor deficiency attenuates pulmonary hypertension through suppression of Rho/TGF-β1 signaling
复制标题
EP3 受体缺陷可通过抑制 Rho/TGF-β1 信号传导来减轻肺动脉高压。
DOI：
10.1172/jci77656
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发表时间：
2015-03-01
影响因子：
15.9
通讯作者：
Yu, Ying
中科院分区：
文献类型：
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作者：
Lu, Ankang;Zuo, Caojian;Yu, Ying
肺动脉高压（PAH）通常与慢性阻塞性肺病（COPD）等疾病中的慢性低氧血症相关。前列环素类似物广泛用于PAH患者的管理;然而，一些前列环素类似物的临床疗效和长期耐受性可能会因E-前列腺素3（EP 3）受体的伴随激活而受损。在这里，我们发现，EP 3表达上调肺动脉平滑肌细胞（PASMCs）和人远端肺动脉（PA）在缺氧反应。在啮齿动物模型中，无论是药理学抑制EP 3还是EP 3缺失都能减弱缺氧和野百合碱诱导的肺动脉高压，并抑制PA中细胞外基质的积累。在小鼠PAH模型中，SMC中的Ep 3缺失，而不是内皮细胞，延迟PA中膜厚度。敲除EP 3 α和EP 3 β，但不敲除EP 3 γ，同种型减少缺氧诱导的TGF-β 1活化。在EP 3缺陷的PASMCs中EP 3 α或EP 3 β的表达恢复了响应缺氧的TGF-β 1活化。PASMCs中的EP 3 α/β激活增加RhoA依赖性膜1型细胞外基质金属蛋白酶（MMP）向细胞表面的移位，随后激活MMP-2前体并促进TGF-β 1信号传导。激活或破坏EP 3不影响PASMC增殖。总之，我们的研究结果表明，EP 3激活促进缺氧诱导的血管重塑和肺动脉高压小鼠，并建议EP 3抑制作为一个潜在的治疗策略肺动脉高压。
Pulmonary arterial hypertension (PAH) is commonly associated with chronic hypoxemia in disorders such as chronic obstructive pulmonary disease (COPD). Prostacyclin analogs are widely used in the management of PAH patients; however, clinical efficacy and long-term tolerability of some prostacyclin analogs may be compromised by concomitant activation of the E-prostanoid 3 (EP3) receptor. Here, we found that EP3 expression is upregulated in pulmonary arterial smooth muscle cells (PASMCs) and human distal pulmonary arteries (PAs) in response to hypoxia. Either pharmacological inhibition of EP3 or Ep3 deletion attenuated both hypoxia and monocrotaline-induced pulmonary hypertension and restrained extracellular matrix accumulation in PAs in rodent models. In a murine PAH model, Ep3 deletion in SMCs, but not endothelial cells, retarded PA medial thickness. Knockdown of EP3 alpha and EP3 beta, but not EP3 gamma, isoforms diminished hypoxia-induced TGF-beta 1 activation. Expression of either EP3 alpha or EP3 beta in EP3-deficient PASMCs restored TGF-beta 1 activation in response to hypoxia. EP3 alpha/beta activation in PASMCs increased RhoA-dependent membrane type1 extracellular matrix metalloproteinase (MMP) translocation to the cell surface, subsequently activating pro-MMP-2 and promoting TGF-beta 1 signaling. Activation or disruption of EP3 did not influence PASMC proliferation. Together, our results indicate that EP3 activation facilitates hypoxia-induced vascular remodeling and pulmonary hypertension in mice and suggest EP3 inhibition as a potential therapeutic strategy for pulmonary hypertension.