SiRNA nanoparticles targeting CaMKIIγ in lesional macrophages improve atherosclerotic plaque stability in mice.
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ABSTRACT:
SUBMITTER: Tao W
PROVIDER: S-EPMC7476570 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Hyaluronan is a biologically active polymer, which can be formulated into nanoparticles. In our study, we aimed to probe atherosclerosis-associated inflammation by using hyaluronan nanoparticles and to determine whether they can ameliorate atherosclerosis. Hyaluronan nanoparticles (HA-NPs) were prepared by reacting amine-functionalized oligomeric hyaluronan (HA) with cholanic ester and labeled with a fluorescent or radioactive label. HA-NPs were characterized in vitro by several advanced microscopy methods. The targeting properties and biodistribution of HA-NPs were studied in apoe-/- mice, which received either fluorescent or radiolabeled HA-NPs and were examined ex vivo by flow cytometry or nuclear techniques. Furthermore, three atherosclerotic rabbits received 89Zr-HA-NPs and were imaged by PET/MRI. The therapeutic effects of HA-NPs were studied in apoe-/- mice, which received weekly doses of 50 mg/kg HA-NPs during a 12-week high-fat diet feeding period. Hydrated HA-NPs were ca. 90 nm in diameter and displayed very stable morphology under hydrolysis conditions. Flow cytometry revealed a 6- to 40-fold higher uptake of Cy7-HA-NPs by aortic macrophages compared to normal tissue macrophages. Interestingly, both local and systemic HA-NP-immune cell interactions significantly decreased over the disease progression. 89Zr-HA-NPs-induced radioactivity in atherosclerotic aortas was 30% higher than in wild-type controls. PET imaging of rabbits revealed 6-fold higher standardized uptake values compared to the muscle. The plaques of HA-NP-treated mice contained 30% fewer macrophages compared to control and free HA-treated group. In conclusion, we show favorable targeting properties of HA-NPs, which can be exploited for PET imaging of atherosclerosis-associated inflammation. Furthermore, we demonstrate the anti-inflammatory effects of HA-NPs in atherosclerosis.
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Project description:Senescent vascular smooth muscle cells (VSMCs) accumulate in the vasculature with age and tissue damage and secrete factors that promote atherosclerotic plaque vulnerability and disease. Here, we report increased levels and activity of dipeptidyl peptidase 4 (DPP4), a serine protease, in senescent VSMCs. Analysis of the conditioned media from senescent VSMCs revealed a unique senescence-associated secretory phenotype (SASP) signature comprising many complement and coagulation factors; silencing or inhibiting DPP4 reduced these factors and increased cell death. Serum samples from persons with high risk for cardiovascular disease contained high levels of DPP4-regulated complement and coagulation factors. Importantly, DPP4 inhibition reduced senescent cell burden and coagulation and improved plaque stability, while single-cell resolution of senescent VSMCs reflected the senomorphic and senolytic effects of DPP4 inhibition in murine atherosclerosis. We propose that DPP4-regulated factors could be exploited therapeutically to reduce senescent cell function, reverse senohemostasis, and improve vascular disease.
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Project description:To elucidate the impact of Trem2 agonist on aortic gene expression during atherosclerosis.
2024-04-18 | GSE256189 | GEO
Project description:BackgroundA direct and independent role of inflammation in atherothrombosis was recently highlighted by the Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) trial, showing the benefit of inhibiting signaling molecules, eg, interleukins. Accordingly, we sought to devise a flexible platform for preventing the inflammatory drivers at their source to preserve plaque endothelium and mitigate procoagulant risk.Methodsp5RHH-siRNA nanoparticles were formulated through self-assembly processes. The therapeutic efficacy of p5RHH-JNK2 siRNA nanoparticles was evaluated both in vitro and in vivo.ResultsBecause JNK2 is critical to macrophage uptake of oxidized lipids through scavenger receptors that engender expression of myriad inflammatory molecules, we designed an RNA-silencing approach based on peptide-siRNA nanoparticles (p5RHH-siRNA) that localize to atherosclerotic plaques exhibiting disrupted endothelial barriers to achieve control of JNK2 expression by macrophages. After seven doses of p5RHH-JNK2 siRNA nanoparticles over 3.5 weeks in ApoE-/- mice on a Western diet, both JNK2 mRNA and protein levels were significantly decreased by 26% (P=0.044) and 42% (P=0.042), respectively. Plaque-macrophage populations were markedly depleted and NF?B and STAT3-signaling pathways inhibited by 47% (P<0.001) and 46% (P=0.004), respectively. Endothelial barrier integrity was restored (2.6-fold reduced permeability to circulating 200 nm nanoparticles in vivo, P=0.003) and thrombotic risk attenuated (200% increased clotting times to carotid artery injury, P=0.02), despite blood-cholesterol levels persistently exceeding 1,000 mg/dL. No adaptive or innate immunoresponses toward the nanoparticles were observed, and blood tests after the completion of treatment confirmed the largely nontoxic nature of this approach.ConclusionThe ability to formulate these nanostructures rapidly and easily interchange or multiplex their oligonucleotide content represents a promising approach for controlling deleterious signaling events locally in advanced atherosclerosis.
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Project description:Atherosclerosis (AS) is characterized as progressive arterial plaque, which is easy to rupture under low stability. Macrophage polarization and inflammation response plays an important role in regulating plaque stability. Ginsenoside Rb1 (Rb1), one of the main active principles of Panax Ginseng, has been found powerful potential in alleviating inflammatory response. However, whether Rb1 could exert protective effects on AS plaque stability remains unclear. This study investigated the role of Rb1 on macrophage polarization and atherosclerotic plaque stability using primary peritoneal macrophages isolated from C57BL/6 mice and AS model in ApoE-/- mice. In vitro, Rb1 treatment promoted the expression of arginase-I (Arg-I) and macrophage mannose receptor (CD206), two classic M2 macrophages markers, while the expression of iNOS (M1 macrophages) was decreased. Rb1 increased interleukin-4 (IL-4) and interleukin-13 (IL-13) secretion in supernatant and promoted STAT6 phosphorylation. IL-4 and/or IL-13 neutralizing antibodies and leflunomide, a STAT6 inhibitor attenuated the up-regulation of M2 markers induced by Rb1. In vivo, the administration of Rb1 promoted atherosclerotic lesion stability, accompanied by increased M2 macrophage phenotype and reduced MMP-9 staining. These data suggested that Rb1 enhanced atherosclerotic plaque stability through promoting anti-inflammatory M2 macrophage polarization, which is achieved partly by increasing the production of IL-4 and/or IL-13 and STAT6 phosphorylation. Our study provides new evidence for possibility of Rb1 in prevention and treatment of atherosclerosis.
| S-EPMC5742675 | biostudies-literature
Project description:Rationale: Abnormal autophagic death of endothelial cells is detrimental to plaque structure as endothelial loss promotes lesional thrombosis. As emerging functional biomarkers, circular RNAs (circRNAs) are involved in various diseases, including cardiovascular. This study is aimed to determine the role of hsa_circ_0030042 in abnormal endothelial cell autophagy and plaque stability. Methods: circRNA sequencing and quantitative polymerase chain reaction were performed to detect hsa_circ_0030042 expression in coronary heart disease (CHD) and human umbilical vein endothelial cells (HUVECs). Transfection of stubRFP-sensGFP-LC3 adenovirus, flow cytometry, and electron microscopy were used to identify the role of hsa_circ_0030042 in ox-LDL‒induced abnormal autophagy in vitro. Bioinformatic analysis, RNA immunoprecipitation, immunofluorescence assay and other in vitro experiments were performed to elucidate the mechanism underlying hsa_circ_0030042-mediated regulation of autophagy. To evaluate the role of hsa_circ_0030042 in atherosclerotic plaques and endothelial function, we measured the carotid artery tension and performed histopathology and immunohistochemistry analysis. Results: hsa_circ_0030042 was significantly downregulated in CHD, while upon overexpression, it acted as an endogenous eukaryotic initiation factor 4A-III (eIF4A3) sponge to inhibit ox-LDL-induced abnormal autophagy of HUVECs and maintain plaque stability in vivo. Furthermore, hsa_circ_0030042 influenced autophagy by sponging eIF4A3 and blocking its recruitment to beclin1 and forkhead box O1 (FOXO1) mRNA, while hsa_circ_0030042-induced inhibition of beclin1 and FOXO1 was counteracted by eIF4A3 overexpression or decreased hsa_circ_0030042 binding. In high-fat-diet fed ApoE-/- mice, hsa_circ_0030042 also ameliorated plaque stability and counteracted eIF4A3-induced plaque instability. Conclusions: These results demonstrate a novel pathway involving hsa_circ_0030042, eIF4A3, FOXO1, and beclin1; hence, modulating their levels may be a potential therapeutic strategy against CHD.
| S-EPMC8039966 | biostudies-literature
Project description:Atherosclerosis is a major cause of global morbidity and mortality that could benefit from novel targeted therapeutics. Recent studies have shown efficient and local drug delivery with nanoparticles, although the nanoparticle targeting mechanism for atherosclerosis has not yet been fully elucidated. Here we used in vivo and ex vivo multimodal imaging to examine permeability of the vessel wall and atherosclerotic plaque accumulation of fluorescently labeled liposomal nanoparticles in a rabbit model. We found a strong correlation between permeability as established by in vivo dynamic contrast enhanced magnetic resonance imaging and nanoparticle plaque accumulation with subsequent nanoparticle distribution throughout the vessel wall. These key observations will enable the development of nanotherapeutic strategies for atherosclerosis.
| S-EPMC4492477 | biostudies-literature
Project description:Macrophages are innate immune cells with great phenotypic plasticity, which allows them to regulate an array of physiological processes such as host defense, tissue repair, and lipid/lipoprotein metabolism. In this proof-of-principle study, we report that macrophages of the M1 inflammatory phenotype can be selectively targeted by model hybrid lipid-latex (LiLa) nanoparticles bearing phagocytic signals. We demonstrate a simple and robust route to fabricate nanoparticles and then show their efficacy through imaging and drug delivery in inflammatory disease models of atherosclerosis and obesity. Self-assembled LiLa nanoparticles can be modified with a variety of hydrophobic entities such as drug cargos, signaling lipids, and imaging reporters resulting in sub-100nm nanoparticles with low polydispersities. The optimized theranostic LiLa formulation with gadolinium, fluorescein and "eat-me" phagocytic signals (Gd-FITC-LiLa) a) demonstrates high relaxivity that improves magnetic resonance imaging (MRI) sensitivity, b) encapsulates hydrophobic drugs at up to 60% by weight, and c) selectively targets inflammatory M1 macrophages concomitant with controlled release of the payload of anti-inflammatory drug. The mechanism and kinetics of the payload discharge appeared to be phospholipase A2 activity-dependent, as determined by means of intracellular Förster resonance energy transfer (FRET). In vivo, LiLa targets M1 macrophages in a mouse model of atherosclerosis, allowing noninvasive imaging of atherosclerotic plaque by MRI. In the context of obesity, LiLa particles were selectively deposited to M1 macrophages within inflamed adipose tissue, as demonstrated by single-photon intravital imaging in mice. Collectively, our results suggest that phagocytic signals can preferentially target inflammatory macrophages in experimental models of atherosclerosis and obesity, thus opening the possibility of future clinical applications that diagnose/treat these conditions. Tunable LiLa nanoparticles reported here can serve as a model theranostic platform with application in various types of imaging of the diseases such as cardiovascular disorders, obesity, and cancer where macrophages play a pathogenic role.
| S-EPMC4874242 | biostudies-literature
Project description:Although research on the treatment of atherosclerosis has progressed recently, challenges remain in developing more effective, safer and transformative strategies for the treatment of atherosclerosis. Nanomaterials have recently played a unique role in many fields, including atherosclerosis treatment. Platelets are common component in the blood. Due to their inherent properties, platelets can target and adhere to atherosclerotic plaques. Ultrasound-targeted microbubble destruction (UTMD) shows great prospects in promoting the efficiency of drug delivery in treating solid tumors. In this study, we explored the possibility that UTMD assists platelet biomimetic rapamycin (RAP)-loaded poly (lactic-co-glycolic acid) (PLGA) nanoparticles (RAP@PLT NPs) in the treatment of atherosclerosis. The biomimetic nano-formulations exhibit better targeting ability to plaques when administered in vivo. Targeted destruction of Sonovue™ in the aortic area further improved the efficiency of targeting plaques. Moreover, the progression of atherosclerotic plaques was inhibited, and the stability of plaques was improved. Together, our study established a novel strategy for targeted delivery of nanoparticles in atherosclerotic plaques, by combining the advantages of the ultrasonic cavitation effect and biomimicking nanoparticles in drug delivery.
| S-EPMC8958035 | biostudies-literature
Project description:PurposeThe cell surface adhesion molecule CD44 plays important roles in the initiation and development of atherosclerotic plaques. We aim to develop nanoparticles that can selectively target CD44 for the non-invasive detection of atherosclerotic plaques by magnetic resonance imaging.MethodsMagnetic glyconanoparticles with hyaluronan immobilized on the surface have been prepared. The binding of these nanoparticles with CD44 was evaluated in vitro by enzyme linked immunosorbent assay, flow cytometry and confocal microscopy. In vivo magnetic resonance imaging of plaques was performed on an atherosclerotic rabbit model.ResultsThe magnetic glyconanoparticles can selectively bind CD44. In T2* weighted magnetic resonance images acquired in vivo, significant contrast changes in aorta walls were observed with a very low dose of the magnetic nanoparticles, allowing the detection of atherosclerotic plaques. Furthermore, imaging could be performed without significant delay after probe administration. The selectivity of hyaluronan nanoparticles in plaque imaging was established by several control experiments.ConclusionsMagnetic nanoparticles bearing surface hyaluronan enabled the imaging of atherosclerotic plaques in vivo by magnetic resonance imaging. The low dose of nanoparticles required, the possibility to image without much delay and the high biocompatibility are the advantages of these nanoparticles as contrast agents for plaque imaging.
| S-EPMC3823634 | biostudies-literature