In:
Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 36, No. suppl_1 ( 2016-05)
Abstract:
Subarachnoid hemorrhage (SAH) affects approximately 30,000 people each year and accounts for 1-7% of all strokes. Current SAH therapies globally affect blood pressure, potentially causing hypotension and reduced cranial perfusion. Alternatively, our approach is to locally reduce constriction of the blood vessels in the brain by targeting heat shock protein 20 (HSP 20) which plays a role in the thin filament pathway for contraction and relaxation. To this end, we developed nanoparticles for delivery of a locked nucleic acid (LNA, LNA-NPs) designed to inhibit miR-320, an endogenous negative regulator of HSP 20 expression in vascular tissue. We hypothesized that LNA-NP-enabled anti-miR-320 therapy would increase HSP 20 expression, reducing vessel contraction and increasing vessel relaxation. LNA-NPs were formulated with a PEGylated, endosomolytic polymer which has been previously optimized for systemic siRNA delivery (Fig. 1A). In this study, LNA-NPs efficiently complexed LNA (Fig. 1B) and formed ~100 nm diameter LNA-loaded nanoparticles (Fig. 1C). Efficient cytosolic delivery of LNA by LNA-NPs resulted in ~2.5-fold (n = 3, Fig. 1D) and 21% (n = 4, Fig. 1E) increased HSP 20 protein expression compared to LNA alone in rat aortic smooth muscle cells and rat aortic vessels, respectively. Functionally, LNA-NP treated tissue showed a 21% reduction in phenylephrine induced contraction relative to maximal 110 mM KCl-induced contraction (n = 4, Fig. 1F). Rat aorta treated with LNA-NPs also showed increased relaxation within the vessels to sodium nitroprusside by 8.1% (n=4, Fig. 1F). In sum, this approach allowed inhibition of miR-320 and direct modulation of HSP 20 in a translationally relevant organ culture model of vascular disease. Future studies will focus on inhibiting miR-320 in human saphenous vein ex vivo and in a pre-clinical model of SAH after systemic delivery.
Type of Medium:
Online Resource
ISSN:
1079-5642
,
1524-4636
DOI:
10.1161/atvb.36.suppl_1.12
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2016
detail.hit.zdb_id:
1494427-3
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