Aortic aneurysms (AA) are degenerative diseases characterized by destruction of arterial architecture and subsequent dilatation that can eventually lead to fatal ruptures. This study is highly relevant to public health because aortic aneurysms are a serious health concern, specifically for the aging population. Moreover, no targeted pharmacologic therapy yet exists, and current treatment for AA is surgical replacement of the diseased artery, known as endovascular stent graft repair. However, reported post-operatory 10 year survival rates can drop to only 50%. The onset and progression of AA are frequently associated with elastin degradation by metalloproteinases (MMPs), which in turn are derived from activated vascular cells and infiltrating inflammatory cells. ? ? We hypothesize that we can greatly reduce elastin degeneration by local delivery of pharmacological agents capable of stabilizing elastin. This would significantly increase the longevity of patients with AA and substantially delay the requirement for surgical interventions. We propose to employ the unique properties of phenolic tannins such as penta-galloylglucose (PGG) to develop a method for reducing elastin degeneration during AA formation. Phenolic tannins bind to vascular elastin, and in so doing they render elastin highly resistant to enzymatic degeneration. ? ? In preparation for animal studies, in Aim 1, we propose to evaluate in vitro safety and efficacy of elastin stabilization with PGG. This will be accomplished by testing in vitro effects of various concentrations of PGG on viability and metabolism of aortic vascular cells. We will then treat pure aortic elastin and separately fresh aorta, with the optimized PGG procedure, and test for resistance to active MMPs and mechanical properties before and after MMP treatment. ? ? In Aim 2, using an aortic injury model that closely mimics human AA formation, we propose to test the efficacy of a single, periaortic application of PGG to stabilize vascular elastin and reduce AA progression. PGG will be applied during early AA formation and later, in a separate experiment, during AA progression. Pharmacological inhibition of AA progression by elastin stabilization has not been previously reported. We expect that PGG delivery to AA will stabilize aortic elastin, reduce tissue degeneration, retard AA expansion and provide prospects for development of clinically applicable therapies, as an adjunct or stand-alone AA therapy. ? ? ?
|Sinha, Aditi; Nosoudi, Nasim; Vyavahare, Naren (2014) Elasto-regenerative properties of polyphenols. Biochem Biophys Res Commun 444:205-11|
|Sinha, Aditi; Shaporev, Aleksey; Nosoudi, Nasim et al. (2014) Nanoparticle targeting to diseased vasculature for imaging and therapy. Nanomedicine 10:1003-12|