Augmented expression of superoxide dismutase 2 mitigates progression and rupture of experimental abdominal aortic aneurysm

Abstract

Rationale: 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. Methods: 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. Results: Using two different murine models of AAA, we show that in vivo augmentation of SOD2 expression via 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. Conclusions: These results confirm that SOD2 plays a pivotal role in the pathogenesis of experimental AAA and identify its potential as a therapeutic target.

Keywords: SOD2 mRNA; abdominal aortic aneurysm; nanomedicine; oxidative stress; proteomics.