Abstract
AimAbdominal aortic aneurysms (AAA) is a life-threatening weakening and expansion of the abdominal aorta due to inflammatory cell infiltration and gradual degeneration of extracellular matrix (ECM). There are no pharmacological therapies to treat AAA. We tested the hypothesis that nanoparticle (NP) therapy that targets degraded elastin and delivers anti-inflammatory, anti-oxidative, and ECM stabilizing agent, pentagalloyl glucose (PGG) will reverse advance stage aneurysm in an elastase-induced mouse model of AAA.Method and resultsPorcine pancreatic elastase (PPE) was applied periadventitially to the infrarenal aorta in mice and AAA was allowed to develop for 14 days. Nanoparticles loaded with PGG (EL-PGG-NPs) were then delivered via IV route at 14-day and 21-day (10 mg/kg of body weight). A control group of mice received no therapy. The targeting of NPs to the AAA site was confirmed with fluorescent dye marked NPs and gold NPs. Animals were sacrificed at 28-d. We found that targeted PGG therapy reversed the AAA by decreasing matrix metalloproteinases MMP-9 and MMP-2, and the infiltration of macrophages in the medial layer. The increase in diameter of the aorta was reversed to healthy controls. Moreover, PGG treatment restored degraded elastic lamina and increased the circumferential strain of aneurysmal aorta to the healthy levels.ConclusionOur results support that site-specific delivery of PGG with targeted nanoparticles can be used to treat already developed AAA. Such therapy can reverse inflammatory markers and restore arterial homeostasis.
Highlights
An abdominal aortic aneurysm (AAA) is the 13th leading cause of death in the elderly
We found that targeted pentagalloyl glucose (PGG) therapy reversed the AAA by decreasing matrix metalloproteinases Matrix metalloproteinase (MMP)-9 and MMP-2, and the infiltration of macrophages in the medial layer
We have shown that polyphenols such as pentagalloyl glucose (PGG) and Epigallocatechin gallate (EGCG) can increase elastin deposition by smooth muscle cells derived from healthy or aneurysmal rat aorta [4]
Summary
An abdominal aortic aneurysm (AAA) is the 13th leading cause of death in the elderly. Green tea polyphenol EGCG was used orally to a rat model of abdominal aortic aneurysm induced by intraluminal infusion of elastase and adventitial simultaneous CaCl2 application where EGCG prevented the progression of AAA [5]. These studies used excessively high oral doses of polyphenols at the onset of AAA induction and showed an only protective effect. We successfully demonstrate that such targeted delivery of pentagalloyl glucose (PGG) restores degraded elastin, reduces MMP activity and infiltration of inflammatory cells, and regresses already developed aneurysms in elastase-induced AAA model
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