Restoring Vascular Smooth Muscle Cell Mitochondrial Function Attenuates Abdominal Aortic Aneurysm in Mice.

Abstract

Background: Abdominal aortic aneurysm (AAA) is a complex vascular pathology without pharmaceutical interventions. This study aimed to evaluate whether restoring vascular smooth muscle cell (VSMC) mitochondrial function could prevent AAA development.

Methods: Ang II (angiotensin II)-induced AAA was established in Ldlr-deficient mice, and the gene expression profiles in abdominal aortic tissues exhibiting varying degrees of severity were analyzed. Synthetic high-density lipoprotein (sHDL) formulated with Apoa1 mimetic peptide and phospholipids was evaluated for the protective effects on VSMC mitochondria. The therapeutic efficacy of sHDL was further investigated in Ang II-infusion and PPE (porcine pancreatic elastase)-induced AAA models.

Results: VSMC mitochondrial damage intensified gradually during AAA development, which was confirmed in distinct AAA animal models and human tissues. sHDL accumulated in the aneurysmatic lesions and restored mitochondrial DNA levels and the expression of genes related to oxidative phosphorylation following Ang II infusion. In mouse primary VSMCs, sHDL maintained mitochondrial homeostasis by suppressing the upregulation of DRP1 (dynamin-related protein 1), a protein involved in mitochondrial fission, reducing the generation of reactive oxygen species, preventing the loss of mitochondrial membrane potential, and preserving mitochondrial respiratory capacity. Administration of sHDL decreased Ang II-induced AAA incidence (control versus treatment, 76% versus 40%; P<0.05) and maximum aortic diameters. The protective effects of sHDL were further validated in the PPE model, with reductions observed in maximum aortic diameters and aortic mitochondrial DNA loss. Post-Ang II infusion, administration of sHDL improved VSMC mitochondrial function and suppressed aneurysm growth in Apoe-deficient mice. Human AAA is characterized by mitochondrial dysfunction, and liver-derived HDL (high-density lipoprotein) components play a pivotal role in regulating gene expression in aortic tissues.

Conclusions: VSMC mitochondrial damage is a pivotal factor in the development of AAA. The utilization of sHDL nanoparticles represents a promising novel therapeutic approach for AAA, aimed at restoring VSMC mitochondrial function.