Dataset Information

Perivascular delivery of Notch 1 siRNA inhibits injury-induced arterial remodeling.

ABSTRACT:

Objectives

To determine the efficacy of perivascular delivery of Notch 1 siRNA in preventing injury-induced arterial remodeling.

Methods and results

Carotid artery ligation was performed to induce arterial remodeling. After 14 days, morphometric analysis confirmed increased vSMC growth and subsequent media thickening and neointimal formation. Laser capture microdissection, quantitative qRT-PCR and immunoblot analysis of medial tissue revealed a significant increase in Notch1 receptor and notch target gene, Hrt 1 and 2 expression in the injured vessels. Perivascular delivery of Notch 1 siRNA by pluronic gel inhibited the injury-induced increase in Notch 1 receptor and target gene expression when compared to scrambled siRNA controls while concomitantly reducing media thickening and neointimal formation to pre-injury, sham-operated levels. Selective Notch 1 knockdown also reversed the injury-induced inhibition of pro-apoptotic Bax expression while decreasing injury-induced anti-apoptotic Bcl-XL expression to sham-operated control levels. In parallel experiments, proliferative cyclin levels, as measured by PCNA expression, were reversed to sham-operated control levels following selective Notch 1 knockdown.

Conclusion

These results suggest that injury-induced arterial remodeling can be successfully inhibited by localized perivascular delivery of Notch 1 siRNA.

SUBMITTER: Redmond EM

PROVIDER: S-EPMC3885538 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Publications

Perivascular delivery of Notch 1 siRNA inhibits injury-induced arterial remodeling.

Redmond Eileen M EM Liu Weimin W Hamm Katie K Hatch Ekaterina E Cahill Paul A PA Morrow David D

PloS one 20140108 1

<h4>Objectives</h4>To determine the efficacy of perivascular delivery of Notch 1 siRNA in preventing injury-induced arterial remodeling.<h4>Methods and results</h4>Carotid artery ligation was performed to induce arterial remodeling. After 14 days, morphometric analysis confirmed increased vSMC growth and subsequent media thickening and neointimal formation. Laser capture microdissection, quantitative qRT-PCR and immunoblot analysis of medial tissue revealed a significant increase in Notch1 recep ...[more]

PMID: 24416200

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Project description:Cold temperatures are associated with increased mortality and morbidity of cardiovascular and pulmonary disease. Cold exposure causes lung inflammation, pulmonary hypertension (PH), and right ventricle hypertrophy, but there is no effective therapy because of unknown mechanism. Here, we investigated whether RNA interference silencing of tumor necrosis factor (TNF)-α decreases cold-induced macrophage infiltration, PH, and pulmonary arterial (PA) remodeling. We found for the first time that continuous cold exposure (5.0°C) increased TNF-α expression and macrophage infiltration in the lungs and PAs right before elevation of right ventricle systolic pressure. The in vivo RNA interference silencing of TNF-α was achieved by intravenous delivery of recombinant AAV-2 carrying TNF-α short hairpin small-interfering RNA 24 hours before cold exposure. Cold exposure for 8 weeks significantly increased right ventricle pressure compared with the warm controls (40.19±4.9 versus 22.9±1.1 mm Hg), indicating that cold exposure caused PH. Cold exposure increased TNF-α, interleukin-6, and phosphodiesterase-1C protein expression in the lungs and PAs and increased lung macrophage infiltration. Notably, TNF-α short hairpin small-interfering RNA prevented the cold-induced increases in TNF-α, interleukin-6, and phosphodiesterase-1C protein expression, abolished lung macrophage infiltration, and attenuated PH (26.28±1.6 mm Hg), PA remodeling, and right ventricle hypertrophy. PA smooth muscle cells isolated from cold-exposed animals showed increased intracellular superoxide levels and cell proliferation along with decreased intracellular cGMP. These cold-induced changes were prevented by TNF-α short hairpin small-interfering RNA. In conclusions, upregulation of TNF-α played a critical role in the pathogenesis of cold-induced PH by promoting pulmonary macrophage infiltration and inflammation. AAV delivery of TNF-α short hairpin small-interfering RNA may be an effective therapeutic approach for cold-induced PH and PA remodeling.

Dataset Information

Perivascular delivery of Notch 1 siRNA inhibits injury-induced arterial remodeling.

Objectives

Methods and results

Conclusion

Publications

Perivascular delivery of Notch 1 siRNA inhibits injury-induced arterial remodeling.

Similar Datasets

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