Peroxiredoxin-2 inhibits abdominal aortic aneurysm formation by resisting ferroptosis through elimination of reactive oxygen species accumulation in vascular smooth muscle cells.

Abstract

Background: Abdominal aortic aneurysm (AAA) is defined as the abnormal and progressive dilation of the abdominal aorta, posing a high mortality risk due to its tendency to expand and eventually rupture. Vascular smooth muscle cells (VSMCs), the predominant cell type in the medial layer of the arterial wall, contribute to AAA development through multiple mechanisms, including ferroptosis, apoptosis, and VSMC reprogramming, etc. Here, we investigate the molecular mechanisms by which ferroptosis affects VSMC function and its role in AAA formation.

Methods: A single-cell RNA sequencing dataset (GSE164678) was downloaded from the GEO database for re-analysis. Ang II was used to induce C57BL/6J mice to establish an AAA model. After injection of peroxiredoxin-2 (PRDX2)-overexpressing VSMCs, the structural integrity of the abdominal aorta, mitochondrial morphology, as well as the levels of Fe 2+ and lipid peroxides were detected. PRDX2-knockdown VSMCs were constructed and treated with catalase (CAT), followed by the detection of reactive oxygen species (ROS) level, cell proliferation, and angiogenic capacity. Finally, PRDX2-overexpressing VSMCs were treated with H 2 O 2 and Erastin in combination, and the changes in ferroptosis-related indicators were determined.

Results: Reanalysis of single-cell RNA sequencing data revealed that PRDX2+ SMCs, a specific subpopulation of smooth muscle cells recruited in AAA, may drive AAA progression through ferroptosis mechanisms. In vivo experiments confirmed that the injection of PRDX2-overexpressing VSMCs alleviated Ang II-induced ferroptosis and inhibited the development of AAA. As a ROS scavenger, PRDX2 effectively suppressed ferroptosis in VSMCs and regulated their proliferation and angiogenic functions.

Conclusion: PRDX2 inhibits the formation of AAA by eliminating intracellular ROS accumulation and suppressing ferroptosis in VSMCs, suggesting that targeting PRDX2 to regulate VSMC ferroptosis represents a potential therapeutic strategy for AAA.