Signaling molecules in nonfamilial pulmonary hypertension.
Signaling molecules in nonfamilial pulmonary hypertension.
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DOI：
10.1056/nejmoa021650
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发表时间：
2003-02-06
影响因子：
158.5
通讯作者：
Thistlethwaite, Patricia A.
中科院分区：
文献类型：
--
作者：
Du, Lingling;Sullivan, Christopher C.;Thistlethwaite, Patricia A.
生物化学、遗传学和临床证据表明，肺小血管周围平滑肌增生是肺动脉高压发病机制的重要组成部分。骨形态发生蛋白受体2（BMPR 2）的突变与肺动脉高压的家族性病例有关，但常见的非家族性形式的分子基础尚不清楚。方法：我们评估了肺动脉高压患者和血压正常对照患者肺活检标本中血管生成素-1（一种参与血管周围平滑肌细胞募集的蛋白质）、血管生成素-1的内皮特异性受体TIE 2、骨形态发生蛋白受体1A（BMPR 1A）和BMPR 2的表达模式。还在人肺小动脉内皮细胞的传代培养中评价了血管生成素-1对BMPR表达的调节作用。结果在各种形式的肺动脉高压患者的肺中，血管生成素-1信使RNA和蛋白质本身的表达以及TIE 2的磷酸化强烈上调，与疾病的严重程度直接相关。家族性肺动脉高压和获得性肺动脉高压之间的机制联系通过血管生成素-1关闭肺小动脉内皮细胞中BMPR 2信号传导所需的跨膜蛋白BMPR 1A的表达这一发现得到证实。同样，我们发现，在各种形式的获得性肺动脉高压和原发性非家族性肺动脉高压患者的肺中，BMPR 1A的表达严重减少。结论：这些发现表明，所有形式的肺动脉高压都与血管生成素-1，TIE 2，BMPR 1A和BMPR 2信号通路的缺陷有关，因此确定了治疗干预的特异性分子靶点。
BACKGROUND Biochemical, genetic, and clinical evidence indicates that smooth-muscle proliferation around small pulmonary vessels is an essential part of the pathogenesis of pulmonary hypertension. Mutations in the bone morphogenetic protein receptor type 2 (BMPR2) have been linked to familial cases of pulmonary hypertension, but the molecular basis of the common nonfamilial forms is unknown. METHODS We evaluated the pattern of expression of angiopoietin-1, a protein involved in the recruitment of smooth-muscle cells around blood vessels; TIE2, the endothelial-specific receptor for angiopoietin-1; and bone morphogenetic protein receptor type 1A (BMPR1A) and BMPR2 in lung-biopsy specimens from patients with pulmonary hypertension and from normotensive control patients. The effect of angiopoietin-1 on the modulation of BMPR expression was also evaluated in subcultures of human pulmonary arteriolar endothelial cells. EESULTS The expression of angiopoietin-1 messenger RNA and the protein itself and the phosphorylation of TIE2 were strongly up-regulated in the lungs of patients with various forms of pulmonary hypertension, correlating directly with the severity of disease. A mechanistic link between familial and acquired pulmonary hypertension was demonstrated by the finding that angiopoietin-1 shuts off the expression of BMPR1A, a transmembrane protein required for BMPR2 signaling, in pulmonary arteriolar endothelial cells. Similarly, we found that the expression of BMPR1A was severely reduced in the lungs of patients with various forms of acquired as well as primary nonfamilial pulmonary hypertension. CONCLUSIONS These findings suggest that all forms of pulmonary hypertension are linked by defects in the signaling pathway involving angiopoietin-1, TIE2, BMPR1A, and BMPR2 and consequently identify specific molecular targets for therapeutic intervention.