Date of Award
Doctor of Philosophy (PhD)
Charles D. Rice
Abdominal aortic aneurysm (AAA) has been the 15th leading cause of death in persons older than 55 for the past ten years in several Western countries, with rupture resulting in an almost 100% mortality rate. AAA is a focal dilation of the aorta characterized by progressive loss of elastin and vascular smooth muscle cells (SMCs), as well as persistent inflammatory response . The only treatment for AAA is surgery; however, the mortality post-procedure is still 1-4%, with a 15-30% chance of morbidity .
Pentagalloyl glucose (PGG) treatment is effective in the reversal of AAA. While its stabilizing interactions with extracellular matrix, such as the elastin protein, have been more thoroughly studied, the cellular mechanisms of PGG are not well understood. Targeted delivery of PGG with albumin nanoparticles surface conjugated to an antibody that targets explicitly degraded elastin (PGG-ELN-NPs), reversed AA growth in rodent models associated with decreased number of macrophages and transforming growth factor beta (TGF-β) expression .
Evidence suggests that macrophages participate in TGF-β signaling feedback and are critical to the progression of cardiovascular diseases. Thus, we hypothesized that PGG can induce anti-inflammatory macrophage polarization, reduce the pathogenic effects induced in vascular cells, and modify TGF-β release. Furthermore, a specific micro-ribonucleic acid (miRNA), miR-29a, which regulates several ECM genes, is downregulated in human thoracic aneurysms and negatively correlated to aortic diameter. Consumption of gallic acid group containing polyphenols like PGG increases expression of miR-29a. Therefore, we also theorized that PGG may influence this miRNA as part of the mechanism of AA reversal and repair [4-6].
First, using human primary vascular cells and THP-1 monocytic cell line, we demonstrate that PGG induces anti-inflammatory macrophage polarization and mitigates the effects of macrophage inflammation on vascular cells. Next, we show that PGG can induce miR-29a-3p expression in immortalized mouse vascular aortic SMCs associated with suppressing angiotensin II-mediated phenotypic modulation. Since we have previously demonstrated the effectiveness of PGG-ELN-NPs in reversing established aneurysms, we next determined the efficacy of these particles in preventing aortic rupture and mortality in two mouse models. Lastly, to facilitate further translation to humans, we established a novel model of abdominal AA in swine with similar characteristics to human AA.
Halsey, Greg, "Cellular Mechanism Of Pentagalloyl Gucose-Mediated Prevention And Reversal Of Abdominal Aortic Aneurysms" (2023). All Dissertations. 3519.