Critical role for the advanced glycation end-products receptor in pulmonary arterial hypertension etiology.
Critical role for the advanced glycation end-products receptor in pulmonary arterial hypertension etiology.
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DOI：
10.1161/jaha.112.005157
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发表时间：
2013-01-16
影响因子：
5.4
通讯作者：
Bonnet S
中科院分区：
文献类型：
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作者：
Meloche J;Courchesne A;Barrier M;Carter S;Bisserier M;Paulin R;Lauzon-Joset JF;Breuils-Bonnet S;Tremblay É;Biardel S;Racine C;Courture C;Bonnet P;Majka SM;Deshaies Y;Picard F;Provencher S;Bonnet S
肺动脉高压（PAH）是一种以肺动脉平滑肌细胞（PASMC）增殖增强和凋亡抑制为特征的血管病变。这导致肺动脉压和肺血管阻力增加。最近的研究表明信号转导和转录激活因子3（STAT 3）/骨形态发生蛋白受体2（BMPR 2）/过氧化物酶体增殖物激活受体γ（PPARγ）在PAH中的作用。STAT 3激活诱导BMPR 2下调，减少PPARγ，这两者都有助于PAH中观察到的促增殖和抗凋亡表型。在软骨细胞中，该轴的激活归因于晚期糖基化终产物受体（Advanced Glycation End Products Receptor，简称AGEs）。由于BMP 2是PAH患者肺中上调最多的蛋白质之一，也是一种强STAT 3激活剂，因此我们假设BMP 2通过激活STAT 3诱导BMP 2和PPARγ下调，从而促进PAH-PASMC增殖和抗凋亡。在体外，使用从PAH和健康患者中分离的PASMC，我们证明了PAH-PASMC中的过表达（6倍增加），从而诱导STAT 3激活（从10%到40%阳性细胞）以及BMPR 2和PPARγ水平降低（>50%降低）。通过S100 A4在对照细胞中药理学激活PAH表型（使PAH增加6倍，从而激活STAT 3并降低BMPR 2和PPARγ）。在这两种情况下，这种表型完全逆转的抑制。在体内，在野百合碱和Sugen诱导的PAH中，抑制β-内酰胺酶显示出治疗作用，其特征在于PA压力和右心室肥大降低（对照大鼠的mPAP约为15 mm Hg，PAH大鼠的mPAP >40 mm Hg，在MCT和Sugen模型中，抑制β-内酰胺酶后，mPAP分别降低至20和28 mm Hg）。这与肺灌注和血管重塑的显著改善相关，因为增殖减少（减少>50%）和BMPR 2/PPARγ轴恢复（增加≥60%）。我们已经证明了PAH病因学中的ESTA的影响。因此，PAH是一个新的有吸引力的治疗靶点。
Pulmonary arterial hypertension (PAH) is a vasculopathy characterized by enhanced pulmonary artery smooth muscle cell (PASMC) proliferation and suppressed apoptosis. This results in both increase in pulmonary arterial pressure and pulmonary vascular resistance. Recent studies have shown the implication of the signal transducer and activator of transcription 3 (STAT3)/bone morphogenetic protein receptor 2 (BMPR2)/peroxisome proliferator‐activated receptor gamma (PPARγ) in PAH. STAT3 activation induces BMPR2 downregulation, decreasing PPARγ, which both contribute to the proproliferative and antiapoptotic phenotype seen in PAH. In chondrocytes, activation of this axis has been attributed to the advanced glycation end‐products receptor (RAGE). As RAGE is one of the most upregulated proteins in PAH patients' lungs and a strong STAT3 activator, we hypothesized that by activating STAT3, RAGE induces BMPR2 and PPARγ downregulation, promoting PAH‐PASMC proliferation and resistance to apoptosis. In vitro, using PASMCs isolated from PAH and healthy patients, we demonstrated that RAGE is overexpressed in PAH‐PASMC (6‐fold increase), thus inducing STAT3 activation (from 10% to 40% positive cells) and decrease in BMPR2 and PPARγ levels (>50% decrease). Pharmacological activation of RAGE in control cells by S100A4 recapitulates the PAH phenotype (increasing RAGE by 6‐fold, thus activating STAT3 and decreasing BMPR2 and PPARγ). In both conditions, this phenotype is totally reversed on RAGE inhibition. In vivo, RAGE inhibition in monocrotaline‐ and Sugen‐induced PAH demonstrates therapeutic effects characterized by PA pressure and right ventricular hypertrophy decrease (control rats have an mPAP around 15 mm Hg, PAH rats have an mPAP >40 mm Hg, and with RAGE inhibition, mPAP decreases to 20 and 28 mm Hg, respectively, in MCT and Sugen models). This was associated with significant improvement in lung perfusion and vascular remodeling due to decrease in proliferation (>50% decrease) and BMPR2/PPARγ axis restoration (increased by ≥60%). We have demonstrated the implications of RAGE in PAH etiology. Thus, RAGE constitutes a new attractive therapeutic target for PAH.