Nanoparticle-mediated targeting of pitavastatin to small pulmonary arteries and leukocytes by intravenous administration attenuates the progression of monocrotaline-induced established pulmonary arterial hypertension in rats

Abstract

Statins are known to improve pulmonary arterial hypertension (PAH) by their anti-inflammatory and anti-proliferative effects in animal models. However, recent clinical studies have reported that clinically approved statin doses failed to improve clinical outcomes in patients with PAH. We therefore hypothesized that nanoparticle (NP)-mediated targeting of pitavastatin could attenuate the progression of established PAH. We induced PAH by subcutaneously injecting monocrotaline (MCT) in Sprague-Dawley rats. On day 14 after the MCT injection, animals that displayed established PAH on echocardiography were included. On day 17, they were randomly assigned to the following 5 groups: daily intravenous administration of (1) vehicle, (2) fluorescein-isothiocyanate-NP, (3) pitavastatin, (4) pitavastatin-NP, or (5) oral sildenafil. Intravenous NP was selectively delivered to small pulmonary arteries and circulating CD11b-positive leukocytes. On day 21, pitavastatin-NP attenuated the progression of PAH at lower doses than pitavastatin alone. This was associated with the inhibition of monocyte-mediated inflammation, proliferation, and remodeling of the pulmonary arteries. Interestingly, sildenafil attenuated the development of PAH, but had no effects on inflammation or remodeling of the pulmonary arteries. In separate experiments, only treatment with pitavastatin-NP reduced the mortality rate at day 35. NP-mediated targeting of pitavastatin to small pulmonary arteries and leukocytes attenuated the progression of established MCT-induced PAH and improved survival. Therapeutically, pitavastatin-NP was associated with anti-inflammatory and anti-proliferative effects on small pulmonary arteries, which was completely distinct from the vasodilatory effect of sildenafil. Pitavastatin-NP can be a novel therapeutic modality for PAH.