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Elastin Stabilization is an Effective and Safe Treatment for Abdominal Aortic Aneurysms (AAAs) in a Rat Model

April 13, 2007

By Laurie Brunette and Asher Kimchi M.D.

Clemson, SC- Currently, a pharmacologic treatment for AAAs does not exist. Present treatment options for this potentially fatal condition include endovascular stents or open surgery, but these procedures are not appropriate for all patients and there are risks involved. One of the characteristic features of AAAs is matrix metalloproteinase (MMP) mediated loss of elastin. However, elastin can be rendered resistant to enzymatic degradation when bound by tannins. Jason C. Isenburg, PhD and Dan T. Simonescu, PhD et al from the Department of Bioengineering at Clemson University in Clemson, SC explored the effects of polyphenolic tannins, specifically petagalloly glucose (PGG), on AAA development. The results of their study, published in the April 3, 2007 issue of Circulation, concluded that acute localized periadventitial delivery of noncytotoxic concentrations of PGG inhibits elastin degradation, attenuates aneurysmal diameter expansion, and hinders development of AAA in an established animal model.

To test the safety and efficacy of PGG, several experiments were done in vitro on cells and arterial extracellular matrix. In vivo experiments involved a CaCl2 injury model of aortic aneurysm. In an experiment to test the effects of PGG on the formation of early AAA, infrarenal abdominal aortas of adult male Sprague-Dawley rats were perivascularly treated for 15 minutes with PGG dissolved in saline on a presoaked gauze applicator. Control rats were treated with saline in the same manner. After rinsing, the abdominal aortas were treated with CaCl2 for 15 minutes. The rats were euthanized 28 days after this procedure and the aortas were excised and analyzed. In a second in vivo experiment to test hindrance of AAA progression, abdominal aortas were treated perivascularly with CaCl2. After 28 days, the aneurysmal aortas of the experimental rats were treated with PGG in saline for 15 minutes, and the control rats were treated with saline. After another 28 days, the rats were euthanized and their aortas were excised for analysis. Aortas were analyzed for desmosine content, elastin content, general histologic structure, PGG content, calcium content, MMP-2 and MMP-9 activity, tissue inhibitor of metalloproteinases [TIMPs] levels, and macrophage and lymphocyte content.

In vitro studies revealed that exposure of cells to PGG concentrations of up to 0.06% had minimal cytotoxic effects and effectively stabilized aortic tissue by binding to elastic fibers. In the first in vivo experiment, it was found that perivascular application of CaCl2 to the infrarenal abdominal aorta of control rats induced a significant increase (42 10% (P<0.05; n=12)) in aortic diameter at 28 days after injury. However, aortas exposed to PGG exhibited a minimal (8 7%) increase in diameter after 28 days. Control aortas demonstrated an almost 50% decrease in elastin content compared to non-surgical controls, while the aortas treated with PGG exhibited only a <15% decrease in elastin content. It was also found that PGG treatment did not result in significant weight loss, hepatotoxicity, or interference with key pathogenic mechanisms typical of this AAA experimental model. In the second in vivo experiment, rat aortas were treated with CaCl2 and AAAs were allowed to develop for 28 days. Control rats were treated with saline at this time and then followed for another 28 days. They showed a total aortic diameter increase of 47.1 11% at 56 days, and half of these aneurysmal aortas significantly increased in diameter from day 28 to 56. Aneurysmal aortas that were exposed to PGG on day 28 exhibited no increase in mean diameter at 56 days compared to with day 28 mean values. It is of note that 100% of the aortas in the PGG group had an aortic diameter that did not change or decreased at 56 days compared to 28 days. These PGG treated aortas also exhibited better preservation of elastic laminar integrity and tissue architecture as compared with controls.

These results demonstrate that periadventitial administration of PGG preserves elastin fiber integrity and 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.

Co-authors: Jason C. Isenburg, Dan T Simonescu, Barry C. Starcher, and Narenda R. Vyavahare

 


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