Nanoparticle-mediated endothelial cell-selective delivery of pitavastatin induces functional collateral arteries (therapeutic arteriogenesis) in a rabbit model of chronic hind limb ischemia

Oda, Shinichiro; Nagahama, Ryoji; Nakano, K.; Matoba, Tetsuya; Kubo, Mitsuki; Sunagawa, Kenji; Tominaga, Ryuji; Egashira, Kensuke

doi:10.1016/j.jvs.2010.03.020

Cited by 37 publications

(44 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

Section: Discussionmentioning

confidence: 99%

“…Recently, we developed a novel nanoparticle-mediated drug-delivery system (DDS) that is formulated from bioabsorbable poly(lactic-co-glycolic) acid (PLGA) polymer, and we reported that nanoparticles were taken up by a variety of cells, such as monocytes, vascular smooth muscle cells, and endothelial cells. In addition, the nanoparticle-mediated DDS showed a significant enhancement in the therapeutic effects on ischemia-induced neovascularization 22,23 and pulmonary arterial hypertension 24 in animal models compared with conventional administration. Nanoparticles are rapidly taken up by circulating monocytes and the mononuclear phagocytic system after intravenous administration, 25 and nano-sized contrast agents accumulate in atherosclerotic plaques.…”

Section: Cd11bmentioning

confidence: 98%

“…The dose of pitavastatin-NPs used in the present study was selected because of its effectiveness in previous studies from our laboratory in murine and rabbit models of hindlimb ischemia. 22,23 Further studies are needed to determine the optimal dose range and interval of pitavastatin-NPs for clinical application.In conclusion, recruitment of inflammatory monocytes is critical in the pathogenesis of plaque destabilization and rupture. Nanoparticle-mediated pitavastatin delivery inhibited plaque destabilization and rupture and regulated the recruitment of inflammatory monocytes by interfering in MCP-1/ CCR2 signaling in this model.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Nanoparticle-Mediated Delivery of Pitavastatin Inhibits Atherosclerotic Plaque Destabilization/Rupture in Mice by Regulating the Recruitment of Inflammatory Monocytes

et al. 2014

Self Cite

View full text Add to dashboard Cite

C oronary heart disease is the leading cause of death worldwide, and at least 7 million patients die of this disease each year (386 324 people in the United States alone).1 Acute myocardial infarction (AMI) is the most severe type of coronary heart disease and the most frequent cause of heart failure, and it impairs the quality of life and inflates medical costs. Timely and successful revascularization therapy for AMI reduces short-term mortality, and current standard medical therapy with angiotensin-converting enzyme inhibitors and β-blockers ameliorates the development of post-myocardial infarction heart failure. However, these recent advances in therapeutic intervention for AMI are associated with an increased prevalence of heart failure with high long-term mortality, which remains a serious concern.2 In the United States, 5.1 million people experienced heart failure in 2010, and 274 601 people died of heart failure in 2009. 1 Therefore, there is an urgent need for preventive treatment to avoid plaque destabilization and rupture, which directly cause AMI. Clinical Perspective on p 906Rupture-prone unstable atherosclerotic plaques feature monocyte/macrophage infiltration, lipid core formation, and fibrous cap thinning by matrix metalloproteinases (MMPs). 3 Recent reports suggest that monocytes are functionally polarized into at least 2 major subsets: Inflammatory monocytes (CD14 high in mice). 4 Inflammatory monocytes are found in the peripheral blood of patients with AMI, 5 Background-Preventing atherosclerotic plaque destabilization and rupture is the most reasonable therapeutic strategy for acute myocardial infarction. Therefore, we tested the hypotheses that (1) inflammatory monocytes play a causative role in plaque destabilization and rupture and (2) the nanoparticle-mediated delivery of pitavastatin into circulating inflammatory monocytes inhibits plaque destabilization and rupture. Methods and Results-We used a model of plaque destabilization and rupture in the brachiocephalic arteries of apolipoprotein E-deficient (ApoE −/− ) mice fed a high-fat diet and infused with angiotensin II. The adoptive transfer of CCR2 +/+ Ly-6C high inflammatory macrophages, but not CCR2 −/− leukocytes, accelerated plaque destabilization associated with increased serum monocyte chemoattractant protein-1 (MCP-1), monocyte-colony stimulating factor, and matrix metalloproteinase-9. We prepared poly(lactic-co-glycolic) acid nanoparticles that were incorporated by Ly-6G − CD11b+ monocytes and delivered into atherosclerotic plaques after intravenous administration. Intravenous treatment with pitavastatin-incorporated nanoparticles, but not with control nanoparticles or pitavastatin alone, inhibited plaque destabilization and rupture associated with decreased monocyte infiltration and gelatinase activity in the plaque. Pitavastatin-incorporated nanoparticles inhibited MCP-1-induced monocyte chemotaxis and the secretion of MCP-1 and matrix metalloproteinase-9 from cultured macrophages. Furthermore, the nanoparticle-mediated a...

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Cd11bmentioning

confidence: 98%

mentioning

confidence: 99%

See 1 more Smart Citation

Nanoparticle-Mediated Delivery of Pitavastatin Inhibits Atherosclerotic Plaque Destabilization/Rupture in Mice by Regulating the Recruitment of Inflammatory Monocytes

et al. 2014

Self Cite

View full text Add to dashboard Cite

show abstract

“…13 We therefore hypothesized that eNOS and downstream pathogenetic factors might be involved in the therapeutic effects of NP-mediated pitavastatin delivery on MCT-induced PAH. Among statins, pitavastatin was selected as the nanoparticulation compound because this drug elicited the most potent angiogenic effects in human endothelial cells 14 and the most potent inhibitory effects on human PASMC proliferation ( Figure 2) in vitro compared with other statins. We also found that NP-mediated intracellular delivery of pitavastatin showed greater inhibitory effects on PASMC proliferation and on NF-B activation in a monocyte cell line (RAW 264.7 cells) compared with pitavastatin alone (online-only Figures III and IV).…”

Section: Discussionmentioning

confidence: 99%

“…Pitavastatin was selected as the nanoparticulation compound because this drug has shown the most potent beneficial effects on human endothelial and smooth muscle cells in vitro compared with other statins. 13,14 We then used a rat model of MCTinduced PAH and examined (1) whether this NP-mediated delivery of pitavastatin into the lung is more effective than intratracheal or systemic administration of pitavastatin in attenuating the development of PAH and (2) whether this NP-mediated delivery system induces regression of established PAH.…”

mentioning

confidence: 99%

Nanoparticle-Mediated Delivery of Pitavastatin Into Lungs Ameliorates the Development and Induces Regression of Monocrotaline-Induced Pulmonary Artery Hypertension

et al. 2011

Self Cite

View full text Add to dashboard Cite

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...

show abstract

Cardiovascular medications in angiogenesis—How to avoid the sting in the tail

Wang

Man

et al. 2012

Intl Journal of Cancer

View full text Add to dashboard Cite

Cancer and cardiovascular disease are the leading causes of death worldwide. Cardiovascular medications have recently been found to have favorable effects also for the treatment of noncardiovascular diseases, including cancer. In this review, we use a reverse bedside‐to‐bench approach to investigate the effects of common cardiovascular medications on tumor angiogenesis and vascular angiogenesis. Aspirin seems to reduce the risk of developing cancer, particularly colon cancer. However, whether the protective influence of aspirin is due to antiangiogenesis effect is still unclear. β‐Blockers, which are normally used to reduce heart rate and prolong diastole, trigger an increase in stretch‐associated release of proangiogenic growth factors thereby inducing angiogenesis. However, according to other studies β‐blockers are able to inhibit angiogenesis via multiplicate mechanisms. Similarly, angiotensin converting enzyme inhibitor and angiotensin II type 1 receptor blocker have controversial effects for the regulation of cell proliferation and angiogenesis. Statins can augment collateral vascular growth in ischemic tissues and restrict the development of cancer. So this topical anti‐inflammatory drug seems to be of high value for further therapy. Finally, suggestions on how this pilot experience may guide the conduct of future preclinical investigations, and clinical trials are discussed.

show abstract

Nanoparticle-mediated endothelial cell-selective delivery of pitavastatin induces functional collateral arteries (therapeutic arteriogenesis) in a rabbit model of chronic hind limb ischemia

Abstract: The nanotechnology platform assessed in this study (nanoparticle-mediated endothelial cell-selective delivery of pitavastatin) may be developed as a clinically feasible and promising strategy for therapeutic arteriogenesis in patients.

Cited by 37 publications

References 34 publications

Nanoparticle-Mediated Delivery of Pitavastatin Inhibits Atherosclerotic Plaque Destabilization/Rupture in Mice by Regulating the Recruitment of Inflammatory Monocytes

Nanoparticle-Mediated Delivery of Pitavastatin Inhibits Atherosclerotic Plaque Destabilization/Rupture in Mice by Regulating the Recruitment of Inflammatory Monocytes

Nanoparticle-Mediated Delivery of Pitavastatin Into Lungs Ameliorates the Development and Induces Regression of Monocrotaline-Induced Pulmonary Artery Hypertension

Cardiovascular medications in angiogenesis—How to avoid the sting in the tail

Contact Info

Product

Resources

About