ADAMTS8 Promotes the Development of Pulmonary Arterial Hypertension and Right Ventricular Failure A Possible Novel Therapeutic Target
ADAMTS8 Promotes the Development of Pulmonary Arterial Hypertension and Right Ventricular Failure A Possible Novel Therapeutic Target
复制标题
DOI：
10.1161/circresaha.119.315398
复制
发表时间：
2019-10-25
影响因子：
20.1
通讯作者：
Shimokawa, Hiroaki
中科院分区：
文献类型：
--
作者：
Omura, Junichi;Satoh, Kimio;Shimokawa, Hiroaki
基本原理：肺动脉高压（pulmonary arterial hypertension，PAH）是以肺动脉平滑肌细胞（pulmonary artery smooth muscle cells，PASMCs）异常增殖、内皮功能障碍和细胞外基质重构为特征的肺血管重构。因此，我们需要阐明一个新的治疗靶点在PAH和RV failure.METHODS和结果：我们进行了基因芯片分析，从PAH患者（PAH-PASMCs）和对照组的PASMCs。我们发现ADAMTS 8（disintegrin and metalloproteinase with thrombospondin motifs 8）是一种在肺和心脏中特异性表达的分泌蛋白，在缺氧诱导的肺动脉高压（PH）小鼠PAH-PASMCs和肺中上调。为了阐明ADAMTS 8在PH中的作用，我们使用血管平滑肌细胞特异性ADAMTS 8敲除小鼠（ADAMTS（Delta SM 22））。与对照组相比，ADAMTS（Delta SM 22）小鼠中缺氧诱导的PH减弱。ADAMTS 8过表达增加PASMC增殖，同时下调AMPK（AMP活化蛋白激酶）。与此相反，ADAMTS 8的缺失减少了PASMC的增殖，AMPK上调。此外，ADAMTS 8的缺失减少了体内和体外缺氧条件下的线粒体碎片化。事实上，从ADAMTS（Delta SM 22）小鼠收获的PASMC证明，Ser 637处的磷酸化DRP-1（动力蛋白相关蛋白1）显著上调，具有更高的丰富基因（Mfn 1和Mfn 2）表达和改善的线粒体功能。此外，重组ADAMTS 8以自分泌/旁分泌方式诱导内皮功能障碍和基质金属蛋白酶活化。接下来，为了阐明ADAMTS 8在RV功能中的作用，我们开发了心肌细胞特异性ADAMTS 8敲除小鼠（ADAMTS 8（Delta alpha MHC））。ADAMTS 8（Delta alpha MHC）小鼠对慢性缺氧的反应显示出改善的RV衰竭。此外，ADAMTS 8（Delta alpha MHC）小鼠显示血管生成增强，RV缺血和纤维化减少。最后，高通量筛选显示，甲苯咪唑，这是用于治疗寄生虫感染，减少ADAMTS 8的表达和细胞增殖PAH-PASMCs和改善PH和RV失败在PH啮齿动物models.CONCLUSIONS：这些结果表明，ADAMTS 8是一个新的治疗靶点在PAH。
RATIONALE: Pulmonary arterial hypertension ( PAH) is characterized by pulmonary vascular remodeling with aberrant pulmonary artery smooth muscle cells (PASMCs) proliferation, endothelial dysfunction, and extracellular matrix remodeling.OBJECTIVE: Right ventricular (RV) failure is an important prognostic factor in PAH. Thus, we need to elucidate a novel therapeutic target in both PAH and RV failure.METHODS AND RESULTS: We performed microarray analysis in PASMCs from patients with PAH (PAH-PASMCs) and controls. We found a ADAMTS8 (disintegrin and metalloproteinase with thrombospondin motifs 8), a secreted protein specifically expressed in the lung and the heart, was upregulated in PAH-PASMCs and the lung in hypoxia-induced pulmonary hypertension (PH) in mice. To elucidate the role of ADAMTS8 in PH, we used vascular smooth muscle cell-specific ADAMTS8-knockout mice (ADAMTS(Delta SM22)). Hypoxia-induced PH was attenuated in ADAMTS(Delta SM22) mice compared with controls. ADAMTS8 overexpression increased PASMC proliferation with downregulation of AMPK (AMP-activated protein kinase). In contrast, deletion of ADAMTS8 reduced PASMC proliferation with AMPK upregulation. Moreover, deletion of ADAMTS8 reduced mitochondrial fragmentation under hypoxia in vivo and in vitro. Indeed, PASMCs harvested from ADAMTS(Delta SM22) mice demonstrated that phosphorylated DRP-1 (dynamin-related protein 1) at Ser637 was significantly upregulated with higher expression of profusion genes (Mfn1 and Mfn2) and improved mitochondrial function. Moreover, recombinant ADAMTS8 induced endothelial dysfunction and matrix metalloproteinase activation in an autocrine/paracrine manner. Next, to elucidate the role of ADAMTS8 in RV function, we developed a cardiomyocyte-specific ADAMTS8 knockout mice (ADAMTS8(Delta alpha MHC)). ADAMTS8(Delta alpha MHC) mice showed ameliorated RV failure in response to chronic hypoxia. In addition, ADAMTS8(Delta alpha MHC) mice showed enhanced angiogenesis and reduced RV ischemia and fibrosis. Finally, high-throughput screening revealed that mebendazole, which is used for treatment of parasite infections, reduced ADAMTS8 expression and cell proliferation in PAH-PASMCs and ameliorated PH and RV failure in PH rodent models.CONCLUSIONS: These results indicate that ADAMTS8 is a novel therapeutic target in PAH.