Elastin Stabilization for Treatment of Abdominal Aortic Aneurysms

Abstract

Background-Maintaining the integrity of arterial elastin is vital for the prevention of abdominal aortic aneurysm (AAA) development. We hypothesized that in vivo stabilization of aortic elastin with pentagalloyl glucose (PGG), an elastin-binding polyphenol, would interfere with AAA development. Methods and Results-Safety and efficacy of PGG treatment were first tested in vitro using cytotoxicity, elastin stability, and PGG-elastin interaction assays. For in vivo studies, the efficacy of PGG was evaluated within a well-established AAA model in rats on the basis of CaCl 2 -mediated aortic injury. With this model, PGG was delivered periadventitially at 2 separate time points during the course of AAA development; aortic diameter, elastin integrity, and other pathological aspects were monitored and evaluated in PGG-treated aortas compared with saline-treated control aortas. Our results show that a one-time periadventitial delivery of noncytotoxic levels of PGG inhibits elastin degeneration, attenuates aneurysmal expansion, and hinders AAA development in rats without interfering with the pathogenic mechanisms typical of this model, namely inflammation, calcification, and high metalloproteinase activities. PGG binds specifically to arterial elastin and, in doing so, preserves the integrity of elastic lamellae despite the presence of high levels of proteinases derived from inflammatory cells. Conclusions-Periadventitial administration of PGG hinders the development of AAA in a clinically relevant animal model. Stabilization of aortic elastin in aneurysm-prone arterial segments offers great potential toward the development of safe and effective therapies for AAAs.

Stabilized Collagen Scaffolds for Heart Valve Tissue Engineering

“…19 Briefly, tissues were stained en-bloc with iron chloride, embedded in Tissue Tek optimal cutting temperature compound (Sakura Finetek, USA Inc., Torrance, CA), and 6-mm-thick sections were counterstained with light green. PGG appears brown with this staining.…”

“…19 Samples were subjected to gelatin zymography using 6 mg of protein per lane alongside molecular weight standards. 22 Intensity of MMP bands (white bands on dark background) were evaluated using densitometry using Gel-Pro Analysis Software (MediaCybernetics, Silver Spring, MD) and expressed as relative density units normalized to protein content.…”

“…40 Recently, we showed that peri-arterial delivery of PGG to rat abdominal aorta prevented aneurysm formation or progression and did not elicit any detectable changes in serum liver enzyme activities or liver histology, showing that PGG was not toxic at the local or systemic level. 19 Moreover, extractables obtained from PGG-fixed tissues exhibited low in vitro cytotoxicity toward fibroblasts and smooth muscle cells 41 and thus can be used safely in tissue-engineering applications. [42][43][44][45][46] In current studies, we have shown that PGG binds strongly to pericardial collagen and that this binding is stable for at least 3 weeks in vivo.…”

Pulmonary heart valve replacement using stabilized acellular xenogeneic scaffolds; effects of seeding with autologous stem cells

“…Valve-derived scaffolds are preferred because of easy accessibility, outstanding hemodynamic properties and the preservation of biological "niches" after decellularization (10)(11)(12). We also treat acellular scaffolds with penta-galloyl glucose (PGG) for tissue stabilization, to prevent premature scaffold degradation and to reduce calcification (13)(14)(15). We chose ADSCs because they are easy to obtain in large numbers and because of their plasticity and ability to differentiate into valve cells (7,16).…”

Assembly and Testing of Stem Cell-Seeded Layered Collagen Constructs for Heart Valve Tissue Engineering

“…In vitro studies showed that PGG, when used in concentrations higher than 0.15%, could be cytotoxic. 46 To achieve an optimum balance of cell viability and scaffold stability, we chose to use 0.1% PGG followed by rinsing and neutralization. PGG treatment of the BTglue was not detrimental to gluing properties, confirming earlier studies that showed that use of glutaraldehyde in conjunction with PGG had a synergistic effect on tissue stabilization.…”