Yan Huimin, Hu Ying, Lyu Yang, Akk Antonina, Hirbe Angela C, Wickline Samuel A, Pan Hua, Roberson Elisha D O, Pham Christine T N
The Department of Medicine, Division of Rheumatology, Washington University School of Medicine, Saint Louis, Missouri, USA.
The John Cochran VA Medical Center, Saint Louis, Missouri USA; The Department of Medicine, Division of Rheumatology, Washington University School of Medicine, Saint Louis, Missouri, USA.
Theranostics. 2025 Mar 10;15(9):4016-4032. doi: 10.7150/thno.104957. eCollection 2025.
Oxidative stress is implicated in the pathogenesis and progression of abdominal aortic aneurysm (AAA). It is suggested that an excess in reactive oxygen species (ROS) over endogenous antioxidant activities can lead to endothelial and mitochondrial dysfunction, which promotes tissue inflammation, extracellular matrix degradation, and cellular apoptosis, all pathologic features characteristic of AAA. While elevated levels of ROS in human and experimental AAA appear well established, the contribution of endogenous antioxidant systems to aneurysm formation and progression remains controversial. We demonstrate that the antioxidant enzyme superoxide dismutase 2 (SOD2), the resident mitochondrial form of SODs that protects against mitochondrial damage, is relatively deficient in established preclinical AAA. We hypothesize that augmented expression of SOD2 will protect against oxidative stress and mitigate aneurysm progression. Herein, we employ a peptide-based nanoplatform to overexpress a key modulator of oxidative stress, SOD2. The efficacy of systemic delivery of murine SOD2 mRNA as an antioxidant nanotherapeutic agent was studied in two different murine AAA models. Unbiased mass spectrometry-enabled proteomics and high-dimensional bioinformatics were used to examine pathways modulated by SOD2 overexpression. Using two different murine models of AAA, we show that augmentation of SOD2 expression mRNA-based nanotherapy mitigates the expansion of small aneurysms and largely prevents rupture. Mitigation of AAA is accompanied by concomitant suppression of ROS, ROS surrogate markers, and apoptotic cell death. Proteomic profiling of AAA tissue and gene set enrichment analysis show that SOD2 overexpression is associated with modulation of oxidative phosphorylation, respiratory electron transport, and fatty acid metabolism. In addition, SOD2 overexpression inhibits platelet activation, downregulates mitogen-activated protein kinase signaling, and augments levels of microRNAs miR-181a-5p and miR17-5p targets that regulate vascular inflammation and cell apoptosis, respectively. These results confirm that SOD2 plays a pivotal role in the pathogenesis of experimental AAA and identify its potential as a therapeutic target.
氧化应激与腹主动脉瘤（AAA）的发病机制和进展有关。有研究表明，活性氧（ROS）过量超过内源性抗氧化活性会导致内皮细胞和线粒体功能障碍，进而促进组织炎症、细胞外基质降解和细胞凋亡，这些都是AAA的病理特征。虽然在人类和实验性AAA中ROS水平升高似乎已得到充分证实，但内源性抗氧化系统对动脉瘤形成和进展的作用仍存在争议。我们发现抗氧化酶超氧化物歧化酶2（SOD2），即驻留在线粒体中防止线粒体损伤的SOD形式，在已建立的临床前AAA中相对缺乏。我们假设SOD2表达增强将抵御氧化应激并减轻动脉瘤进展。在此，我们采用基于肽的纳米平台来过表达氧化应激的关键调节因子SOD2。在两种不同的小鼠AAA模型中研究了作为抗氧化纳米治疗剂全身递送小鼠SOD2 mRNA的疗效。使用无偏质谱蛋白质组学和高维生物信息学来检查由SOD2过表达调节的通路。使用两种不同的小鼠AAA模型，我们表明基于mRNA的纳米疗法增强SOD2表达可减轻小动脉瘤的扩张并在很大程度上防止破裂。AAA的减轻伴随着ROS、ROS替代标志物和凋亡细胞死亡的同时抑制。AAA组织的蛋白质组分析和基因集富集分析表明，SOD2过表达与氧化磷酸化、呼吸电子传递和脂肪酸代谢的调节有关。此外，SOD2过表达抑制血小板活化，下调丝裂原活化蛋白激酶信号传导，并增加分别调节血管炎症和细胞凋亡的微小RNA miR-181a-5p和miR17-5p靶标的水平。这些结果证实SOD2在实验性AAA的发病机制中起关键作用，并确定了其作为治疗靶点的潜力。
