Role of Stromelysin 2 (Matrix Metalloproteinase 10) as a Novel Mediator of Vascular Remodeling Underlying Pulmonary Hypertension Associated With Systemic Sclerosis
Role of Stromelysin 2 (Matrix Metalloproteinase 10) as a Novel Mediator of Vascular Remodeling Underlying Pulmonary Hypertension Associated With Systemic Sclerosis
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DOI：
10.1002/art.40229
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发表时间：
2017-11-01
影响因子：
13.3
通讯作者：
Allanore, Yannick
中科院分区：
文献类型：
--
作者：
Avouac, Jerome;Guignabert, Christophe;Allanore, Yannick
目标。目的阐明与系统性硬化症(SSC)相关的肺动脉高压(PH)相关的候选基因的作用。通过在Affymetrix基因芯片人类外显子1.0 ST阵列上进行微阵列实验，在内皮祖细胞(EPC)来源的内皮细胞(ECs)中鉴定候选基因，这些内皮细胞来自SSC相关性PH患者、SSC非PH患者和健康对照组。用血清定量夹心酶联免疫吸附试验和免疫组织化学方法检测确定的候选基因的表达。然后在FOS相关抗原2转基因(Fra-2-TG)小鼠中评估识别的候选基因的功能重要性，这些小鼠自发地产生与强烈的肺血管重建相关的SSC样特征。基因芯片实验表明，基质金属蛋白酶10(MMP10)基因是SSC相关的PH EPC来源的ECs中最高表达的基因。SSC相关PH患者的循环血清proMMP10浓度明显高于无PH的SSC患者和健康对照组。与这些观察结果一致的是，在SSc相关性PH患者的肺和Fra-2-TG小鼠的肺中，都发现远端肺动脉壁增厚的MMP10强烈染色。中和性抗MMP10抗体对Fra-2-Tg小鼠肺纤维化的发展和严重程度无明显影响，但通过减少细胞增殖、细胞存活和血小板衍生生长因子信号轴，逆转已建立的肺高压，并显著减少肺血管重塑。EPC来源的内皮细胞的基因表达谱证实MMP10是SSC相关PH的一个新的候选基因。MMP10在SSc相关性PH患者的血清和肺动脉中过表达，其阻断可减轻Fra-2-TG小鼠模型中的PH。MMP10似乎是这种破坏性疾病的潜在治疗靶点。
Objective. To elucidate the role of gene candidates involved in pulmonary hypertension (PH) associated with systemic sclerosis (SSc).Methods. Gene candidates were identified through microarray experiments performed on Affymetrix Gene-Chip Human Exon 1.0 ST arrays in endothelial progenitor cell (EPC)-derived endothelial cells (ECs) obtained from patients with SSc-associated PH, patients with SSc without PH, and healthy control subjects. Expression of identified gene candidates was assessed by quantitative sandwich enzyme-linked immunosorbent assay in the serum, and by immunohistochemistry in lesional lung tissue. The functional importance of the identified gene candidates was then evaluated in fos-related antigen 2-transgenic (Fra-2-Tg) mice that spontaneously develop SSc-like features associated with an intense pulmonary vascular remodeling.Results. Microarray experiments revealed that the matrix metalloproteinase 10 (MMP-10) gene was the top up-regulated gene in SSc-associated PH EPC-derived ECs. Circulating serum proMMP10 concentrations were markedly increased in patients with SSc-associated PH compared to SSc patients without PH and healthy controls. Consistent with these observations, a strong MMP10 staining of the thickened wall of distal pulmonary arteries was found both in the lungs of patients with SSc-associated PH and in the lungs of Fra-2-Tg mice. Daily treatment of Fra-2-Tg mice with neutralizing anti-MMP10 antibodies did not significantly affect the development and severity of pulmonary fibrosis, but did reverse established PH and markedly reduced pulmonary vascular remodeling by reducing cell proliferation, cell survival, and the platelet-derived growth factor signaling axis.Conclusion. Gene expression profiling of EPC-derived ECs identified MMP10 as a novel candidate gene in SSc-associated PH. MMP10 is overexpressed in the serum and pulmonary arteries of patients with SSc-associated PH, and its blockade alleviates PH in the Fra-2-Tg mouse model. MMP10 appears to be a prospective treatment target for this devastating disorder.