A critical role for Egr-1 during vascular remodelling in pulmonary arterial hypertension
A critical role for Egr-1 during vascular remodelling in pulmonary arterial hypertension
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DOI：
10.1093/cvr/cvu169
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发表时间：
2014-09-01
影响因子：
10.8
通讯作者：
Berger, Rolf M. F.
中科院分区：
文献类型：
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作者：
Dickinson, Michael G.;Kowalski, Piotr S.;Berger, Rolf M. F.
目的肺动脉高压（PAH）的特征是小肺动脉中独特的新生内膜病变的发展，导致右心室（RV）后负荷增加和衰竭。需要针对这些新生内膜病变的新的治疗策略。最近，转录因子Egr-1（早期生长反应蛋白1）被证明在实验性新生内膜PAH的早期上调。然而，它对疾病发展的影响尚不清楚。我们的目的是发现一个新的作用Egr-1作为一个分子诱导剂的疾病发展在PAH.Methods和结果在实验流量相关的肺动脉高压大鼠，我们研究了Egr-1下调对肺血管重塑的影响，包括新生内膜的发展，和疾病的进展。静脉注射催化性寡脱氧核苷酸（DNA酶，DNAzymes）导致肺血管Egr-1表达下调。与载体或乱序DNA酶相比，DNA酶减弱肺血管重塑，包括闭塞性新生内膜病变的发展。体内Egr-1的选择性下调导致血管PDGF-β、TGF-β、IL-6和p53的表达减少，导致血管增殖减少和凋亡增加。DNAzyme治疗进一步减弱肺血管阻力、RV收缩压和RV肥大。相反，在非新生内膜PH啮齿动物中，DNAzyme治疗对肺血管和RV重塑没有影响。最后，药理学抑制Egr-1与吡格列酮，过氧化物酶体增殖物激活受体-G配体，衰减血管重塑，包括发展的neointimal lesions.Conclusions这些结果表明，Egr-1管理肺血管重塑和发展的特征性血管新生内膜病变的流量相关的PAH。因此，Egr-1是未来PAH治疗的潜在靶点。
Aims Pulmonary arterial hypertension (PAH) is characterized by the development of unique neointimal lesions in the small pulmonary arteries, leading to increased right ventricular (RV) afterload and failure. Novel therapeutic strategies are needed that target these neointimal lesions. Recently, the transcription factor Egr-1 (early growth response protein 1) was demonstrated to be up-regulated early in experimental neointimal PAH. Its effect on disease development, however, is unknown. We aimed to uncover a novel role for Egr-1 as a molecular inductor for disease development in PAH.Methods and results In experimental flow-associated PAH in rats, we investigated the effects of Egr-1 down-regulation on pulmonary vascular remodelling, including neointimal development, and disease progression. Intravenous administration of catalytic oligodeoxynucleotides (DNA enzymes, DNAzymes) resulted in down-regulation of pulmonary vascular Egr-1 expression. Compared with vehicle or scrambled DNAzymes, DNAzymes attenuated pulmonary vascular remodelling, including the development of occlusive neointimal lesions. Selective down-regulation of Egr-1 in vivo led to reduced expression of vascular PDGF-beta, TGF-beta, IL-6, and p53, resulting in a reduction of vascular proliferation and increased apoptosis. DNAzyme treatment further attenuated pulmonary vascular resistance, RV systolic pressure, and RV hypertrophy. In contrast, in non-neointimal PH rodents, DNAzyme treatment had no effect on pulmonary vascular and RV remodelling. Finally, pharmacological inhibition of Egr-1 with pioglitazone, a peroxisome proliferator activated receptor-g ligand, attenuated vascular remodelling including the development of neointimal lesions.Conclusions These results indicate that Egr-1 governs pulmonary vascular remodelling and the development of characteristic vascular neointimal lesions in flow-associated PAH. Egr-1 is therefore a potential target for future PAH treatment.