Altered Bone Morphogenetic Protein and Transforming Growth Factor-β Signaling in Rat Models of Pulmonary Hypertension Potential for Activin Receptor-Like Kinase-5 Inhibition in Prevention and Progression of Disease
Altered Bone Morphogenetic Protein and Transforming Growth Factor-β Signaling in Rat Models of Pulmonary Hypertension Potential for Activin Receptor-Like Kinase-5 Inhibition in Prevention and Progression of Disease
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DOI：
10.1161/circulationaha.108.821504
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发表时间：
2009-02-03
期刊：
影响因子：
37.8
通讯作者：
Morrell, Nicholas W.
中科院分区：
文献类型：
--
作者：
Long, Lu;Crosby, Alexi;Morrell, Nicholas W.
最近的遗传学研究强调了骨形态发生蛋白(BMP)/转化生长因子(TGF)- β信号通路在家族性肺动脉高压（PAH）发病机制中的作用。目前尚不清楚这些通路的改变是否会导致其他形式的肺动脉高压，以及这些改变在多大程度上可以用于治疗干预。方法与结果：我们研究了2种慢性缺氧和多环芳烃大鼠模型中BMP/ tgf - β信号转导。在这两种模型中，肺BMP IA型受体和BMP II型受体mRNA表达均显著降低，尽管这些变化在单苦杏仁碱模型中更为明显。与此同时，在单芥碱模型中，肺中phospho-Smad1/5和Id （DNA结合抑制剂）基因表达水平降低。相比之下，我们观察到tgf - β活性增加，在单杏仁氨酸模型中再次更加明显，这可以通过磷酸化smad2 /3的增加和tgf - β调节基因的表达增加来证明。免疫组化结果显示，大鼠肺动脉平滑肌细胞和肺动脉重构周围巨噬细胞中tgf - β(1)表达升高。选择性小分子抑制剂in -1233在体内抑制激活素受体样激酶-5信号传导，可防止单蔓榄碱注射后PAH、右心室肥厚和血管重构，并抑制该模型中建立的PAH的进展。缺氧多环芳烃组无明显影响。体外研究证实，tgf - β刺激大鼠远端肺动脉平滑肌细胞的迁移，而In -1233可抑制这一作用。结论：与慢性缺氧模型相比，多环芳烃模型中BMP/ tgf - β信号的破坏更为明显。增加tgf - β活性与巨噬细胞招募增加有关。通过激活素受体样激酶-5抑制tgf - β信号传导可在单罗塔碱模型中阻止PAH的发生和进展，并可能涉及抑制肺动脉平滑肌细胞迁移。(循环。2009;119:566 - 576)。
Background-Recent genetic studies have highlighted the role of the bone morphogenetic protein (BMP)/transforming growth factor (TGF)-beta signaling pathways in the pathogenesis of familial pulmonary arterial hypertension (PAH). It remains unclear whether alterations in these pathways contribute to other forms of pulmonary hypertension and to what extent these changes can be exploited for therapeutic intervention.Methods and Results-We studied BMP/TGF-beta signaling in 2 rat models of PAH due to chronic hypoxia and monocrotaline. In both models, there was a significant reduction in lung BMP type IA receptor and BMP type II receptor mRNA expression, although these changes were more pronounced in the monocrotaline model. This was accompanied by a reduction in lung levels of phospho-Smad1/5 and Id (inhibitor of DNA binding) gene expression in the monocrotaline model. In contrast, we observed increased TGF-beta activity, again more marked in the monocrotaline model, as evidenced by increased phospho-Smad2/3 and increased expression of TGF-beta-regulated genes. Immunohistochemistry revealed increased TGF-beta(1) expression in pulmonary artery smooth muscle cells and macrophages surrounding remodeled pulmonary arteries in monocrotaline rats. Inhibition of activin receptor-like kinase-5 signaling in vivo with the selective small-molecule inhibitor IN-1233 prevented PAH, right ventricular hypertrophy, and vascular remodeling after monocrotaline injection and inhibited the progression of established PAH in this model. No significant effect was observed in hypoxic PAH. In vitro studies confirmed that TGF-beta stimulated migration of distal rat pulmonary artery smooth muscle cells and that this effect was inhibited by IN-1233.Conclusions-Disruption of BMP/TGF-beta signaling is more pronounced in the monocrotaline model of PAH than in the chronic hypoxia model. Increased TGF-beta activity is associated with greater macrophage recruitment with monocrotaline treatment. Inhibition of TGF-beta signaling via activin receptor-like kinase-5 prevents development and progression of PAH in the monocrotaline model and may involve inhibition of pulmonary artery smooth muscle cell migration. (Circulation. 2009;119:566-576.)