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...

Background: Chronic kidney disease (CKD) increases cardiovascular risk. Underlying mechanisms, however, remain obscure. The uremic toxin indoxyl sulfate is an independent cardiovascular risk factor in CKD. We explored the potential impact of indoxyl sulfate on pro-inflammatory activation of macrophages and its underlying mechanisms. Methods: We examined in viro the effects of clinically relevant concentrations of indoxyl sulfate on pro-inflammatory responses of macrophages and the roles of organic anion transporters (OATs) and organic anion transporting polypeptides (OATPs). A systems approach, involving unbiased global proteomics, bioinformatics, and network analysis, then explored potential key pathways. To address the role of Dll4 in indoxyl sulfate-induced macrophage activation and atherogenesis in CKD in vivo, we used 5/6 nephrectomy and Delta-like 4 (Dll4) antibody in LDL receptor-deficient (Ldlr−/−) mice. To further determine the relative contribution of OATP2B1 or Dll4 to pro-inflammatory activation of macrophages and atherogenesis in vivo, we used siRNA delivered by macrophage-targeted lipid nanoparticles in mice. Results: We found that indoxyl sulfate-induced pro-inflammatory macrophage activation is mediated by its uptake through transporters, including OATP2B1, encoded by the SLCO2B1 gene. The global proteomics identified potential mechanisms, including Notch signaling and the ubiquitin-proteasome pathway, that mediate indoxyl sulfate-triggered pro-inflammatory macrophage activation. We chose the Notch pathway as an example of key candidates for validation of our target discovery platform and for further mechanistic studies. As predicted computationally, indoxyl sulfate triggered Notch signaling, which was preceded by the rapid induction of Dll4 protein. Dll4 induction may result from inhibition of the ubiquitin-proteasome pathway, via the deubiquitinating enzyme USP5. In mice, macrophage-targeted OATP2B1/Slco2b1 silencing and Dll4 antibody inhibited pro-inflammatory activation of peritoneal macrophages induced by indoxyl sulfate. In Ldlr−/− mice, Dll4 antibody abolished atherosclerotic lesion development accelerated in CKD mice. Moreover, co-administration of indoxyl sulfate and OATP2B1/Slco2b1 or Dll4 siRNA encapsulated in macrophage-targeted lipid nanoparticles in Ldlr−/− mice suppressed lesion development. Conclusion: These results suggest that novel crosstalk between OATP2B1 and Dll4-Notch signaling in macrophages mediates indoxyl sulfate-induced vascular inflammation in CKD.

Objective-Inflammatory monocytes/macrophages produce various proteinases, including matrix metalloproteinases, and degradation of the extracellular matrix by these activated proteinases weakens the mechanical strength of atherosclerotic plaques, which results in a rupture of the plaque. Peroxisome proliferator-activated receptor-γ induces a polarity shift of monocytes/macrophages toward less inflammatory phenotypes and has the potential to prevent atherosclerotic plaque ruptures. Therefore, we hypothesized that nanoparticle-mediated targeted delivery of the peroxisome proliferatoractivated receptor-γ agonist pioglitazone into circulating monocytes could effectively inhibit plaque ruptures in a mouse model. Approach and Results-We prepared bioabsorbable poly(lactic-co-glycolic-acid) nanoparticles containing pioglitazone (pioglitazone-NPs). Intravenously administered poly(lactic-co-glycolic-acid) nanoparticles incorporated with fluorescein isothiocyanate were found in circulating monocytes and aortic macrophages by flow cytometric analysis. Weekly intravenous administration of pioglitazone-NPs (7 mg/kg per week) for 4 weeks decreased buried fibrous caps, a surrogate marker of plaque rupture, in the brachiocephalic arteries of ApoE −/− mice fed a high-fat diet and infused with angiotensin II. In contrast, administration of control-NPs or an equivalent dose of oral pioglitazone treatment produced no effects. Pioglitazone-NPs inhibited the activity of matrix metalloproteinases and cathepsins in the brachiocephalic arteries. Pioglitazone-NPs regulated inflammatory cytokine expression and also suppressed the expression of extracellular matrix metalloproteinase inducer in bone marrow-derived macrophages. Conclusions-Nanoparticle-mediated delivery of pioglitazone inhibited macrophage activation and atherosclerotic plaque ruptures in hyperlipidemic ApoE −/− mice. These results demonstrate a promising strategy with a favorable safety profile to prevent atherosclerotic plaque ruptures.

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Myocardial ischemia-reperfusion (IR) injury limits the therapeutic effect of early reperfusion therapy for acute myocardial infarction (AMI), in which the recruitment of inflammatory monocytes plays a causative role. Here we develop bioabsorbable poly-lactic/glycolic acid (PLGA) nanoparticles incorporating irbesartan, an angiotensin II type 1 receptor blocker with a peroxisome proliferator-activated receptor (PPAR)γ agonistic effect (irbesartan-NP). In a mouse model of IR injury, intravenous PLGA nanoparticles distribute to the IR myocardium and monocytes in the blood and in the IR heart. Single intravenous treatment at the time of reperfusion with irbesartan-NP (3.0 mg kg−1 irbesartan), but not with control nanoparticles or irbesartan solution (3.0 mg kg−1), inhibits the recruitment of inflammatory monocytes to the IR heart, and reduces the infarct size via PPARγ-dependent anti-inflammatory mechanisms, and ameliorates left ventricular remodeling 21 days after IR. Irbesartan-NP is a novel approach to treat myocardial IR injury in patients with AMI.

Coronary artery disease, in the development of which inflammation mediated by innate immune cells plays a critical role, is one of the leading causes of death worldwide. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are a widely used lipid-lowering drug that has lipid-independent vasculoprotective effects, such as improvement of endothelial dysfunction, antioxidant properties, and inhibitory effects on inflammation. Despite recent advances in lipid-lowering therapy, clinical trials of statins suggest that anti-inflammatory therapy beyond lipid-lowering therapy is indispensible to further reduce cardiovascular events. One possible therapeutic option to the residual risk is to directly intervene in the inflammatory process by utilizing a nanotechnology-based drug delivery system (nano-DDS). Various nano-sized materials are currently developed as DDS, including micelles, liposomes, polymeric nanoparticles, dendrimers, carbon nanotubes, and metallic nanoparticles. The application of nano-DDS to coronary artery disease is a feasible strategy since the inflammatory milieu enhances incorporation of nano-sized materials into mononuclear phagocytic system and permeability of target lesions, which confers nano-DDS on “passive-targeting” property. Recently, we have developed a polymeric nanoparticle-incorporating statin to maximize its anti-inflammatory property. This statin nanoparticle has been tested in various disease models, including plaque destabilization and rupture, myocardial ischemia-reperfusion injury, and ventricular remodeling after acute myocardial infarction, and its clinical application is in progress. In this review, we present current development of DDS and future perspective on the application of anti-inflammatory nanomedicine to treat life-threatening cardiovascular diseases.

Influences of reflow time and strain rate on interfacial fracture behaviors of Sn-4Ag/Cu solder joints J. Appl. Phys. 112, 064508 (2012) Early stages of mechanical deformation in indium phosphide with the zinc blende structure J. Appl. Phys. 112, 063514 (2012) Elucidating the mechanism for indentation size-effect in dielectrics Hardness, yield strength, and plastic flow in thin film metallic-glass J. Appl. Phys. 112, 053516 (2012) Development of nondestructive non-contact acousto-thermal evaluation technique for damage detection in materials Rev. Sci. Instrum. 83, 095103 (2012) Additional information on J. Appl. Phys.A mechanism explaining the breakdown of dielectrics with high intrinsic inhomogeneity like natural rocks and concrete is proposed and proved experimentally. This work has a very promising industrial application in the drilling and demolition of natural and artificial solid materials by electric pulses. The mechanism includes the breakdown of gas cavities inside the dielectric and on its surface. At a very high applied voltage, the high electric field causes the breakdown in the cavities. The displacement and conduction currents flowing through a number of such cavities result in the heating of the plasma and high pressure pulse generation. The pulsed pressure results in crack formation and finally, in the destruction of a solid material.

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