From the Department of Pediatrics, Division of Neonatology, Cardiovascular Research Center, Children's Research Institute (A.S., R.-J.T., G.G.K., A.J.A.), Medical College of Wisconsin, Milwaukee, WI.
Department of Pediatrics (A.S., O.A.O., R.-J.T., S.N.K., G.G.K., A.J.A.), Children Hospital of Wisconsin, Milwauke.
Hypertension. 2019 Oct;74(4):957-966. doi: 10.1161/HYPERTENSIONAHA.119.13430. Epub 2019 Sep 3.
Persistent pulmonary hypertension of the newborn (PPHN) is a failure of pulmonary vascular resistance to decline at birth rapidly. One principal mechanism implicated in PPHN development is mitochondrial oxidative stress. Expression and activity of mitochondrial SOD2 (superoxide dismutase) are decreased in PPHN; however, the mechanism remains unknown. Recently, OLA1 (Obg-like ATPase-1) was shown to act as a critical regulator of proteins controlling cell response to stress including Hsp70, an obligate chaperone for SOD2. Here, we investigated whether OLA1 is causally linked to PPHN. Compared with controls, SOD2 expression is reduced in distal-pulmonary arteries (PAs) from patients with PPHN and fetal-lamb models. Disruptions of the gene reproduced PPHN phenotypes, manifested by elevated right ventricular systolic pressure, PA-endothelial cells apoptosis, and PA-smooth muscle cells proliferation. Analyses of SOD2 protein dynamics revealed higher ubiquitinated-SOD2 protein levels in PPHN-lambs, suggesting dysregulated protein ubiquitination. OLA1 controls multiple proteostatic mechanisms and is overexpressed in response to stress. We demonstrated that OLA1 acts as a molecular chaperone, and its activity is induced by stress. Strikingly, OLA1 expression is decreased in distal-PAs from PPHN-patients and fetal-lambs. OLA1 deficiency enhanced CHIP affinity for Hsp70-SOD2 complexes, facilitating SOD2 degradation. Consequently, mitochondrial HO formation is impaired, leading to XIAP (X-linked inhibitor of apoptosis) overexpression that suppresses caspase activity in PA-smooth muscle cells, allowing them to survive and proliferate, contributing to PA remodeling. In-vivo, o downregulated SOD2 expression, induced distal-PA remodeling, and right ventricular hypertrophy. We conclude that decreased OLA1 expression accounts for SOD2 downregulation and, therefore, a therapeutic target in PPHN treatments.
新生儿持续性肺动脉高压（PPHN）是指肺血管阻力在出生时不能迅速下降。在 PPHN 的发展中，一个主要的机制涉及到线粒体氧化应激。PPHN 中表达和活性的线粒体 SOD2（超氧化物歧化酶）减少；然而，其机制尚不清楚。最近，OLA1（Obg 样 ATP 酶-1）被证明是一种关键的调节蛋白，控制着包括 Hsp70 在内的细胞对压力的反应，Hsp70 是 SOD2 的必需伴侣。在这里，我们研究了 OLA1 是否与 PPHN 有因果关系。与对照组相比，PPHN 患者和胎儿羊模型的远端肺动脉（PAs）中 SOD2 的表达减少。基因的破坏重现了 PPHN 的表型，表现为右心室收缩压升高、PA 内皮细胞凋亡和 PA 平滑肌细胞增殖。对 SOD2 蛋白动力学的分析显示，PPHN 羔羊中泛素化 SOD2 蛋白水平升高，提示蛋白质泛素化失调。OLA1 控制多种蛋白质稳态机制，并在应激反应中过度表达。我们证明 OLA1 作为一种分子伴侣，其活性受应激诱导。引人注目的是，PPHN 患者和胎儿羊的远端-PAs 中 OLA1 的表达减少。OLA1 缺乏增强了 CHIP 与 Hsp70-SOD2 复合物的亲和力，促进了 SOD2 的降解。因此，线粒体 HO 的形成受损，导致 XIAP（凋亡的 X 连锁抑制剂）过度表达，抑制了 PA 平滑肌细胞中的 caspase 活性，使它们能够存活和增殖，导致 PA 重塑。在体内，下调 SOD2 的表达，诱导远端-PA 重塑和右心室肥厚。我们得出结论，OLA1 表达的减少导致 SOD2 的下调，因此是 PPHN 治疗的一个治疗靶点。
