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