Endothelial miR-34a deletion guards against aneurysm development despite endothelial dysfunction

Abstract

We previously reported a link between NRF2, a cytoprotective transcription factor, and the ageing of endothelial cells (ECs) and aorta. We also found that NRF2 KO mice are more susceptible to the development of abdominal aortic aneurysm (AAA), which is an age-associated condition. Since miR-34a is a marker of ageing, we explored its relationship with NRF2 and its role in vascular function and AAA formation.

Here, we demonstrate that premature NRF2-dependent ageing of ECs is mediated by miR-34a. Infusion of hypertensive angiotensin II (Ang II) in mice increases miR-34a in the aortic endothelial layer and serum, particularly in mice developing AAA. Mice lacking endothelial miR-34a exhibit severe EC dysfunction. Despite that, they are protected from AAA, also on the NRF2 KO background. This protective effect is reversed by rapamycin, which suppresses Ang II-induced EC proliferation. We identified MTA2, but not SIRT1, as a target of miR-34a that inhibits EC proliferation stimulated by Ang II. These findings suggest that fine-tuning of EC proliferation could have potential therapeutic implications for the treatment of aneurysms.