Elastin stabilization for treatment of abdominal aortic aneurysms.
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.


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 CaCl2-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.
Isenburg
Jason C
JC
Department of Bioengineering, Clemson University, Clemson, SC 29634, USA.
Simionescu
Dan T
DT
Starcher
Barry C
BC
Vyavahare
Narendra R
NR
D000287:Administration, Topical; D000818:Animals; D001012:Aorta, Abdominal / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D002114:Calcinosis / Q000139:chemically induced / Q000209:etiology; D002122:Calcium Chloride / Q000633:toxicity; D002478:Cells, Cultured / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D004353:Drug Evaluation, Preclinical; D004549:Elastin / Q000187:drug effects*; D005347:Fibroblasts / Q000187:drug effects; D047348:Hydrolyzable Tannins / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000032:analysis; D020780:Matrix Metalloproteinase 9 / Q000032:analysis; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects; D011489:Protein Denaturation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
D047348:Hydrolyzable Tannins; C435084:pentagalloylglucose; D004549:Elastin; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D002122:Calcium Chloride