Synthetic High-density Lipoprotein Attenuates Abdominal Aortic Aneurysm Formation Via Restoring Vascular Smooth Muscle Cell Mitochondrial Function

Rationale: Abdominal aortic aneurysm (AAA) is a complex degenerative vascular disease with higher mortality due to aneurysm expansion and ruptures. Extensive mitochondrial dysfunction in aortic VSMC is a prominent feature of AAA. Although HDL (high-density lipoprotein) exerts AAA protective effects, the role of HDL in protecting against VSMC mitochondrial dysfunction during AAA development is not completely understood. Objectives: To evaluate the therapeutic potential of synthesized HDL (sHDL) on AAA and to investigate the underlying mechanisms. Methods and Results: Using an angiotensin II (Ang II)-induced AAA model in Ldlr -/- (low-density lipoprotein receptor-deficient) mice, we found mitochondrial dysfunction was progressively induced during AAA development in the affected aorta segments (suprarenal aortic segments). Two sample mendelian randomization analysis using genetic data from Global Lipids Genetics Consortium and Global Biobank Meta-analysis Initiative consortium revealed a negative association between plasma HDL level and AAA risk. Administration of sHDL (30 mg/kg, three times per week via intraperitoneal injection) significantly reduced the incidence rate of AAA (Vehicle vs sHDL, 76% vs 40%, n=15-17 per group, p<0.05) and the maximum aortic diameter. Mitochondrial DNA copy number in the affected aorta segments is reduced in the vehicle group and can be restored by sHDL treatment. We found the accumulation of sHDL in the aneurysmatic lesions by IVIS imaging, and sHDL reduces AAA-related mitochondrial dysfunction in vivo. Using primary mouse VSMCs, we show that sHDL can maintain mitochondria homeostasis by inhibiting mitochondria fission, reducing ROS production, and inhibiting mitochondrial membrane potential loss upon AAA-related pathologic stimuli. sHDL also significantly inhibits mitochondria DNA release and inflammatory responses in VSMC. Conclusions: The study concludes that sHDL nanoparticles may be a potential new therapeutic avenue for AAA by maintaining vascular smooth muscle cell mitochondrial homeostasis and inhibiting inflammatory responses.