Abstract-Pulmonary arterial hypertension (PAH) is an intractable disease of the small pulmonary artery that involves multiple inflammatory factors. We hypothesized that a redox-sensitive transcription factor, nuclear factor B (NF-B), which regulates important inflammatory cytokines, plays a pivotal role in PAH. We investigated the activity of NF-B in explanted lungs from patients with PAH and in a rat model of PAH. We also examined a nanotechnology-based therapeutic intervention in the rat model. Immunohistochemistry results indicated that the activity of NF-B increased in small pulmonary arterial lesions and alveolar macrophages in lungs from patients with PAH compared with lungs from control patients. In a rat model of monocrotaline-induced PAH, single intratracheal instillation of polymeric nanoparticles (NPs) resulted in delivery of NPs into lungs for Յ14 days postinstillation. The NP-mediated NF-B decoy delivery into lungs prevented monocrotaline-induced NF-B activation. Blockade of NF-B by NP-mediated delivery of the NF-B decoy attenuated inflammation and proliferation and, thus, attenuated the development of PAH and pulmonary arterial remodeling induced by monocrotaline. Treatment with the NF-B decoy NP 3 weeks after monocrotaline injection improved the survival rate as compared with vehicle administration. In conclusion, these data suggest that NF-B plays a primary role in the pathogenesis of PAH and, thus, represent a new target for therapeutic intervention in PAH. This nanotechnology platform may be developed as a novel molecular approach for treatment of PAH in the future.

Abstract-Pulmonary artery hypertension (PAH) is an intractable disease of the small PAs in which multiple pathogenic factors are involved. Statins are known to mitigate endothelial injury and inhibit vascular remodeling and inflammation, all of which play crucial roles in the pathogenesis of PAH. We tested the hypothesis that nanoparticle (NP)-mediated delivery of pitavastatin into the lungs can be a novel therapeutic approach for the treatment of PAH. Among the marketed statins, pitavastatin was found to have the most potent effects on proliferation of PA smooth muscle cells in vitro. We formulated pitavastatin-NP and found that pitavastatin-NP was more effective than pitavastatin alone in inhibiting cellular proliferation and inflammation in vitro. In a rat model of monocrotaline-induced PAH, a single intratracheal instillation of NP resulted in the delivery of NP into alveolar macrophages and small PAs for up to 14 days after instillation. Intratracheal treatment with pitavastatin-NP, but not with pitavastatin, attenuated the development of PAH and was associated with a reduction of inflammation and PA remodeling. NP-mediated pitavastatin delivery was more effective than systemic administration of pitavastatin in attenuating the development of PAH. Importantly, treatment with pitavastatin-NP 3 weeks after monocrotaline injection induced regression of PAH and improved survival rate. This mode of NP-mediated pitavastatin delivery into the lungs is effective in attenuating the development of PAH and inducing regression of established PAH, suggesting potential clinical significance for developing a new treatment for PAH. Key Words: pulmonary hypertension Ⅲ nanotechnology Ⅲ pitavastatin Ⅲ inflammation Ⅲ leukocytes P ulmonary artery hypertension (PAH) is an intractable disease of the small PAs resulting in progressive increases in pulmonary vascular resistance, right ventricular (RV) failure, and ultimately premature death. 1,2 Mortality from PAH remains high, even after introduction of vasodilator therapies such as prostacyclin infusion, endothelin receptor antagonists, and phosphodiesterase inhibitors (which have raised the 5-year survival rate to Ϸ50%). Although these drugs were originally developed for non-PAH vascular diseases, they were introduced into treatment for clinical PAH on the basis of the vasodilator hypothesis. Therefore, a new idea that might lead to a breakthrough curative treatment for PAH is urgently needed.In addition to vasoconstriction, other multiple factors (endothelial injury/apoptosis, obstructive vascular remodeling, proliferation, and inflammation) play an important role in the mechanism of PAH. 1,2 Therefore, we hypothesized that a controlled, local delivery system targeting a battery of those pathogenic factors intrinsic to PAH pathology would be a favorable therapeutic approach with high translational potential to clinical medicine. In this respect, we focused on the vasculoprotective effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, the so-called statins. Stati...

NP-mediated cell-selective statin delivery may be a more effective and integrative strategy for therapeutic neovascularization in patients with severe organ ischemia.

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Therefore, this NP-eluting stent is an efficient NP-mediated DDS that holds as an innovative platform for the delivery of less invasive nano-devices targeting cardiovascular disease.

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Background-Clinical outcome of surgical revascularization using autologous vein graft is limited by vein graft failure attributable to neointima formation. Platelet-derived growth factor (PDGF) plays a central role in the pathogenesis of vein graft failure. Therefore, we hypothesized that nanoparticle (NP)-mediated drug delivery system of PDGF-receptor (PDGF-R) tyrosine kinase inhibitor (imatinib mesylate: STI571) could be an innovative therapeutic strategy. Methods and Results-Uptake of STI571-NP normalized PDGF-induced cell proliferation and migration. Excised rabbit jugular vein was treated ex vivo with PBS, STI571 only, FITC-NP, or STI571-NP, then interposed back into the carotid artery position. NP was detected in many cells in the neointima and media at 7 and 28 days after grafting. Significant neointima was formed 28 days after grafting in the PBS group; this neointima formation was suppressed in the STI571-NP group. STI571-NP treatment inhibited cell proliferation and phosphorylation of the PDGF-R-␤ but did not affect inflammation and endothelial regeneration. Conclusions-STI571-NP-induced

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