Intraluminal infusion of Penta-Galloyl Glucose reduces abdominal aortic aneurysm development in the elastase rat model

Abstract

Background An abdominal aortic aneurysm (AAA) is a progressive chronic dilatation of the abdominal aorta with terminally rupture when the aortic wall is so weakened that aortic wall stress exceeds wall strength. No effective medical treatment exists so far. We aimed to test whether intraluminal admission of Penta-Galloyl Glucose (PGG) treatment in a rodent AAA model could hold the potential to inhibit aneurysmal progression. Method Male Sprague Dawley rats had either intraluminal elastase infused for AAA induction or saline to serve as controls. In two independent experimental series, elastase was used to induce AAA followed by an intraluminal PGG (directly or by a drug eluting balloon) treatment. All rats were followed for 28 days and euthanized. In both series, maximal infrarenal aortic diameter was measured at baseline and at termination as a measure of AAA size. In series 2, maximal internally AAA diameter was followed by ultrasound weekly. AAA tissues were analyzed for elastin integrity by millers stain, collagen deposition by masson trichrome staining. In other AAA tissue samples the mRNA level of CD45, lysyloxidase (LOX), lysyloxidase like protein 1 (LOXL1) were determined by qPCR. Results Direct administration of PGG significantly reduced AAA expansion when compared to controls. PGG treatment resulted in a higher number and more preserved elastic fibers in the aneurysmal wall, while no significant difference was seen in the levels of CD45 and LOX mRNA levels. The drug eluting balloon (DEB) experiment showed no significant difference in AAA size observed neither macroscopically nor ultrasonically. Also the aneurysmal mRNA levels of CD45, LOX and LOXL1 were unchanged between groups.

Animal Model Dependent Response to Pentagalloyl Glucose in Murine Abdominal Aortic Injury

“…As the number of elastin lamellae in the aortic media increases allometrically with animal size [ 44 ], the typical mouse has only three to five layers in the abdominal aorta [ 45 ]. While our periadventitial elastase mouse model showed no differences between control and PGG-treated animals, others have shown PGG’s efficacy in a pressurized intraluminal infusion elastase rat model [ 18 ]. Overall, the findings presented here and in previous reports suggest that the experimental animal model, species size, and number of elastin lamellae should be considered carefully when evaluating biomechanical stabilization.…”

“…However, direct periadventitial application would be technically difficult for patients not undergoing an open laparotomy and nearly impossible for patients treated with EVAR. Nonetheless, others have demonstrated PGG’s efficacy using nanoparticle-based approaches in rats [ 11 , 12 ] and surgical intraluminal pressure infusion in pigs and rats [ 15 , 16 , 18 ]. It is difficult to compare the different approaches to PGG delivery, as each method has its own merits and shortcomings.…”

“…Here, we used mice due to the many well-established aortic injury and aneurysm models in this species. Still, it appears that PGG efficacy may depend on body size and initial aortic thickness, as studies demonstrating its efficacy appear to be more common in pigs and rats [ 8 , 11 , 12 , 13 , 15 , 16 , 18 ]. As the number of elastin lamellae in the aortic media increases allometrically with animal size [ 44 ], the typical mouse has only three to five layers in the abdominal aorta [ 45 ].…”

“…Others have explored alternative delivery methods: Thirugnanasambandam et al utilized the periadventitial application of PGG to CaCl 2 -induced rat aneurysms and found that it was able to lower biomechanical stresses and MMP expressions [ 13 ]. A more recent study by Schack et al [ 18 ] used a rat elastase model to demonstrate preservation of the elastic lamina through intraluminal delivery of PGG via a drug-eluting catheter.…”

Osteopontin N-Terminal Function in an Abdominal Aortic Aneurysm From Apolipoprotein E-Deficient Mice

“…Sections of human aortic tissue were also used. Aortic sections were stained with hematoxylin and eosin (H&E) for morphological assessment in accordance with the standard procedure (Cui et al, 2019;Schack et al, 2020). The elastic fiber integrity of the abdominal aorta was visualized using Masson's trichrome and EVG staining kit (Servicebio Biotechnology Co., Ltd., Wuhan, China) according to the manufacturer's instructions.…”