scholarly journals Inhibiting macrophage proliferation suppresses atherosclerotic plaque inflammation

2015 ◽  
Vol 1 (3) ◽  
pp. e1400223 ◽  
Author(s):  
Jun Tang ◽  
Mark E. Lobatto ◽  
Laurien Hassing ◽  
Susanne van der Staay ◽  
Sarian M. van Rijs ◽  
...  
Keyword(s):  
Atherosclerotic Plaque ◽  
Statin Treatment ◽  
Atherosclerotic Plaques ◽  
Rapid Reduction ◽  
Therapeutic Benefits ◽  
Plaque Inflammation ◽  
Deficient Mice ◽  
Plaque Macrophage ◽  
Macrophage Accumulation

Inflammation drives atherosclerotic plaque progression and rupture, and is a compelling therapeutic target. Consequently, attenuating inflammation by reducing local macrophage accumulation is an appealing approach. This can potentially be accomplished by either blocking blood monocyte recruitment to the plaque or increasing macrophage apoptosis and emigration. Because macrophage proliferation was recently shown to dominate macrophage accumulation in advanced plaques, locally inhibiting macrophage proliferation may reduce plaque inflammation and produce long-term therapeutic benefits. To test this hypothesis, we used nanoparticle-based delivery of simvastatin to inhibit plaque macrophage proliferation in apolipoprotein E–deficient mice (Apoe−/−) with advanced atherosclerotic plaques. This resulted in the rapid reduction of plaque inflammation and favorable phenotype remodeling. We then combined this short-term nanoparticle intervention with an 8-week oral statin treatment, and this regimen rapidly reduced and continuously suppressed plaque inflammation. Our results demonstrate that pharmacologically inhibiting local macrophage proliferation can effectively treat inflammation in atherosclerosis.

scholarly journals Effective atherosclerotic plaque inflammation inhibition with targeted drug delivery by hyaluronan conjugated atorvastatin nanoparticles

Nanoscale ◽  
2020 ◽  
Vol 12 (17) ◽  
pp. 9541-9556 ◽  
Author(s):  
Seyedmehdi Hossaini Nasr ◽  
Zahra Rashidijahanabad ◽  
Sherif Ramadan ◽  
Nate Kauffman ◽  
Narayanan Parameswaran ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Atherosclerotic Plaque ◽  
Targeted Drug Delivery ◽  
Atherosclerotic Plaques ◽  
Plaque Inflammation ◽  
Targeted Drug

Atherosclerosis is associated with inflammation in the arteries. Hyaluronan atorvastatin nanoparticle conjugate could target CD44 overexpressed in atherosclerotic plaques and significantly reduce plaque associated inflammation.

scholarly journals The Role of Matrix Metalloproteinase-9 in Atherosclerotic Plaque Instability

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Tiewei Li ◽  
Xiaojuan Li ◽  
Yichuan Feng ◽  
Geng Dong ◽  
Yuewu Wang ◽  
...  
Keyword(s):  
Matrix Metalloproteinase ◽  
Atherosclerotic Plaque ◽  
Predictive Biomarker ◽  
Matrix Metalloproteinase 9 ◽  
Atherosclerotic Plaques ◽  
Plaque Instability ◽  
Cerebrovascular Events ◽  
Plaque Inflammation ◽  
Metalloproteinase 9

Matrix metalloproteinase-9 (MMP-9) belongs to the MMP family and has been widely investigated. Excessive MMP-9 expression can enhance extracellular matrix degradation and promote plaque instability. Studies have demonstrated that MMP-9 levels are higher in vulnerable plaques than in stable plaques. Additionally, several human studies have demonstrated that MMP-9 may be a predictor of atherosclerotic plaque instability and a risk factor for future adverse cardiovascular and cerebrovascular events. MMP-9 deficiency or blocking MMP-9 expression can inhibit plaque inflammation and prevent atherosclerotic plaque instability. All of these results suggest that MMP-9 may be a useful predictive biomarker for vulnerable atherosclerotic plaques, as well as a therapeutic target for preventing atherosclerotic plaque instability. In this review, we describe the structure, function, and regulation of MMP-9. We also discuss the role of MMP-9 in predicting and preventing atherosclerotic plaque instability.

scholarly journals Overexpression of Prolyl-4-Hydroxylase-α1 Stabilizes but Increases Shear Stress-Induced Atherosclerotic Plaque in Apolipoprotein E-Deficient Mice

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Xiao-qing Cao ◽  
Xin-xin Liu ◽  
Meng-meng Li ◽  
Yu Zhang ◽  
Liang Chen ◽  
...  
Keyword(s):  
Shear Stress ◽  
Atherosclerotic Plaque ◽  
Carotid Arteries ◽  
Coronary Thrombosis ◽  
Oscillatory Shear ◽  
Potential Therapeutic Target ◽  
Fibrous Cap ◽  
Oscillatory Shear Stress ◽  
Deficient Mice ◽  
Macrophage Accumulation

The rupture and erosion of atherosclerotic plaque can induce coronary thrombosis. Prolyl-4-hydroxylase (P4H) plays a central role in the synthesis of all known types of collagens, which are the most abundant constituent of the extracellular matrix in atherosclerotic plaque. The pathogenesis of atherosclerosis is thought to be in part caused by shear stress. In this study, we aimed to investigate a relationship between P4Hα1 and shear stress-induced atherosclerotic plaque. Carotid arteries of ApoE−/− mice were exposed to low and oscillatory shear stress conditions by the placement of a shear stress cast for 2 weeks; we divided 60 male ApoE−/− mice into three groups for treatments with saline (mock) (n=20), empty lentivirus (lenti-EGFP) (n=20), and lentivirus-P4Hα1 (lenti-P4Hα1) (n=20). Our results reveal that after 2 weeks of lenti-P4Hα1 treatment both low and oscillatory shear stress-induced plaques increased collagen and the thickness of fibrous cap and decreased macrophage accumulation but no change in lipid accumulation. We also observed that overexpression of P4Ha1 increased plaque size. Our study suggests that P4Hα1 overexpression might be a potential therapeutic target in stabilizing vulnerable plaques.

Abstract 80: Early Intervention With High-Dose Statin Decreased the Plaque in Acute Stroke Patients With Intracranial Atherosclerosis: High-Resolution MR Wall Imaging Study

Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
Sookyung Ryoo ◽  
Suk Jae Kim ◽  
Jihoon Cha ◽  
Gyeong Joon Moon ◽  
Gyeong-Moon Kim ◽  
...  
Keyword(s):  
Early Intervention ◽  
Statin Therapy ◽  
Atherosclerotic Plaque ◽  
Statin Treatment ◽  
Plaque Burden ◽  
Atherosclerotic Plaques ◽  
High Dose ◽  
Intracranial Atherosclerosis ◽  
Stroke Patients ◽  
Before And After

Intracranial atherosclerosis (ICAS) is a common stroke etiology, especially in Asians. Current guidelines emphasize statin therapy with intensive lipid lowering effects for risk reduction in atherosclerotic strokes. High-dose statin therapy regress coronary, carotid and aortic atherosclerotic plaques. However the role of statin in patients with ICAS remains unknown. Thus we aimed to evaluate the impact of early intervention with rosuvastatin (20mg/day) on the symptomatic intracranial atherosclerotic plaque, using high-resolution (HR) wall MRI. Fiffteen patients with acute infarcts caused by ICAS were enrolled. All patients were given high-dose statin, rosuvastatin 20mg/day and performed serial HR MRI with 3-T scanner including proton density/T2-weighted axial/sagittal, T1 FLAIR pre- and post-contrast sagittal/axial and 3-dimensional volumetric isotropic turbo spin echo acquisition images. Serial HR wall MRI were taken before and after 3~6 months of treatment (interval, 141±45 days). Intracranial artery at the maximal stenosis on MRA was analyzed in terms of vascular remodeling (plaque burden) and wall enhancement (plaque activation). Normal vessels were also assessed for reference values. Intracranial atherosclerotic plaques were compared before and after statin treatment. Both intracranial atherosclerotic plaque burden and activation can be regressed by high-dose statin therapy (Figure). Wall area, a representative of plaque burden, was decreased (pre- vs. post-statin treatment, 5.74±2.63mm2 vs. 4.64±2.58mm2; p=0.027). Enhanced area within the wall, an indicator of plaque activation, was also lowered (pre- vs. post-statin treatment, 3.46±2.15mm2 vs. 2.32±1.81mm2; p=0.013). No patients stop rosuvastatin during follow-up period. Early intervention with high-dose rosuvastatin in acute stroke patients with ICAS enabled significant reduction of the symptomatic intracranial atherosclerotic plaque during 6 months.

Immunization of LDL receptor-deficient mice with β2-glycoprotein 1 or human serum albumin induces a more inflammatory phenotype in atherosclerotic plaques

2007 ◽  
Vol 97 (01) ◽  
pp. 129-138 ◽  
Author(s):  
Sylvie Dunoyer-Geindre ◽  
Brenda Kwak ◽  
Graziano Pelli ◽  
Isabelle Roth ◽  
Nathalie Satta ◽  
...  
Keyword(s):  
Human Serum Albumin ◽  
Serum Albumin ◽  
Abdominal Aorta ◽  
Antiphospholipid Antibodies ◽  
Ldl Receptor ◽  
Statin Treatment ◽  
Atherosclerotic Plaques ◽  
Lesion Development ◽  
Inflammatory Phenotype ◽  
Deficient Mice

SummaryAntiphospholipid antibodies are a risk factor for venous and arterial thrombosis and may contribute to the development of atherosclerosis. The aim of this study was to investigate whether antibodies to human β2-glycoprotein 1 (β2 GP1), as a model of antiphospholipid antibodies, modify the phenotype of atherosclerotic lesions. LDL receptor-deficient mice were immunized with human β2 GP1, human serum albumin (HSA), or not immunized, and fed a high-cholesterol diet for 14 weeks. Some mice also received pravastatin. Immunization with human β2 GP1 or HSA resulted in formation of autoantibodies recognizing murine β2 GP1 or murine albumin, respectively. We quantified atherosclerotic lesion development and mRNA levels of inflammationassociated proteins in the thoraco-abdominal aorta as well as lesion development, cellular composition and collagen content in the aortic roots. Immunization with β2 GP1 or HSA had no effect on lesion size, but modified the expression in plaque areas of several inflammation-associated proteins. Expression of matrix metalloproteinase-9, tissue factor, interferon-gamma and CD25 was highest in the thoraco-abdominal aorta of β2 GP1-immunized mice, lowest in non-immunized mice and intermediate in HSA-immunized animals. Immunization with β2 GP1, but not HSA, resulted in a lower smooth muscle cell and collagen content of lesions in aortic roots. Statin treatment partially reversed the effects of β2 GP1 immunization. We conclude that immunization with β2 GP1, and to a lesser extent with HSA, leads to modifications in the cellular and protein composition of atherosclerotic plaques, which are associated with a more inflammatory phenotype. Statin treatment partially prevents these changes.

Abstract 142: Rac2 Modulates Macrophage IL-1β Production, Atherosclerotic Plaque Inflammation, and Calcific Atherosclerosis

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Nicolle M Ceneri ◽  
Bryan D Young ◽  
Timur O Yarovinsky ◽  
Mehran Sadeghi ◽  
Jeffrey R Bender ◽  
...  
Keyword(s):  
Atherosclerotic Plaque ◽  
Near Infrared ◽  
Therapeutic Potential ◽  
Ex Vivo ◽  
Regulatory Elements ◽  
Aortic Tissue ◽  
Atherosclerotic Plaques ◽  
Pathologic Finding ◽  
Plaque Inflammation ◽  
Aortic Plaques

Ischemic heart disease caused by atherosclerosis is the leading cause of morbidity and mortality in the world. Calcification of atherosclerotic plaques is a well-described pathologic finding that has predictive value in terms of atherosclerotic burden, cardiovascular event risk, and mortality. Inflammation is critical to atherogenesis, but inflammatory mechanisms that drive atherosclerotic calcification are minimally understood. The Rho/Rac family of low molecular weight GTPases regulates the activation, recruitment, and differentiation of monocytes. Racs compete for similar regulatory elements, indicating that targeted modulation of specific family members may influence the role of other members in biologic processes. The hypothesis is that Rac2 can modulate atherosclerotic plaque inflammation and calcium composition via consequent effects on the activation of Rac1. Rac2 gene deletion results in elevated activation (GTP-binding) of Rac1 in macrophages. Increased activation of Rac1 is associated with higher macrophage IL-1β production in response to LPS-coupled cholesterol crystal exposure. In fact, macrophage IL-1β production is dependent on Rac1. When subjected to a high fat diet for 14 weeks, Rac2 -/-ApoE -/- mice demonstrate similar weight gain, serum cholesterol levels, circulating inflammatory monocyte levels, and aortic atherosclerotic lipid burden relative to Rac2 +/+ApoE -/- mice. Atherosclerotic plaques from Rac2 -/-ApoE -/- mice contain increased inflammatory cellular infiltration by histology and relative RNA expression. Ex vivo microCT imaging reveals calcified aortic plaques, and quantification of calcification by near-infrared imaging demonstrates increased calcium composition in plaques from Rac2 -/-ApoE -/- mice relative to Rac2 +/+ApoE -/- mice. Calcified aortic plaques are associated with an increase in IL-1β mRNA expression in the aortic tissue. In summary, Rac2 is a critical modulator of signaling mechanisms that regulate the activation state of Rac1, resulting in enhanced macrophage IL-1β expression in vitro and inflammatory calcification of atherosclerotic plaques in vivo. Targeting the balance of Rac regulation has therapeutic potential in modulation of atherosclerotic plaque composition.

scholarly journals Dental pulp stem cells can improve muscle dysfunction in animal models of Duchenne muscular dystrophy

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yuko Nitahara-Kasahara ◽  
Mutsuki Kuraoka ◽  
Posadas Herrera Guillermo ◽  
Hiromi Hayashita-Kinoh ◽  
Yasunobu Maruoka ◽  
...  
Keyword(s):  
Stem Cells ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Dental Pulp ◽  
Systemic Treatment ◽  
Dental Pulp Stem Cells ◽  
Mri Findings ◽  
Systemic Injection ◽  
Therapeutic Benefits

Abstract Background Duchenne muscular dystrophy (DMD) is an inherited progressive disorder that causes skeletal and cardiac muscle deterioration with chronic inflammation. Dental pulp stem cells (DPSCs) are attractive candidates for cell-based strategies for DMD because of their immunosuppressive properties. Therefore, we hypothesized that systemic treatment with DPSCs might show therapeutic benefits as an anti-inflammatory therapy. Methods To investigate the potential benefits of DPSC transplantation for DMD, we examined disease progression in a DMD animal model, mdx mice, by comparing them with different systemic treatment conditions. The DPSC-treated model, a canine X-linked muscular dystrophy model in Japan (CXMDJ), which has a severe phenotype similar to that of DMD patients, also underwent comprehensive analysis, including histopathological findings, muscle function, and locomotor activity. Results We demonstrated a therapeutic strategy for long-term functional recovery in DMD using repeated DPSC administration. DPSC-treated mdx mice and CXMDJ showed no serious adverse events. MRI findings and muscle histology suggested that DPSC treatment downregulated severe inflammation in DMD muscles and demonstrated a milder phenotype after DPSC treatment. DPSC-treated models showed increased recovery in grip-hand strength and improved tetanic force and home cage activity. Interestingly, maintenance of long-term running capability and stabilized cardiac function was also observed in 1-year-old DPSC-treated CXMDJ. Conclusions We developed a novel strategy for the safe and effective transplantation of DPSCs for DMD recovery, which included repeated systemic injection to regulate inflammation at a young age. This is the first report on the efficacy of a systemic DPSC treatment, from which we can propose that DPSCs may play an important role in delaying the DMD disease phenotype.

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