Adenovirus-mediated gene transfer of a secreted decoy human macrophage scavenger receptor (SR-AI) in LDL receptor knock-out mice

Jalkanen, Johanna; Leppänen, Pia; Närvänen, Outi; Greaves, David R.; Ylä‐Herttuala, Seppo

doi:10.1016/s0021-9150(03)00155-2

Cited by 33 publications

(22 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Uptake of oxidized LDL (ox-LDL) particles by macrophages, mediated primarily by cell-surface scavenger receptors (SRs), is an important pathway of foam cell formation. Interruption of this pathway in cell culture and in animal models blocks foam cell formation, thereby reducing atherogenesis (11,12). But alternative pathways of lipid uptake have also been proposed.…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, macrophage SRs also play atheroprotective roles in both early and late phases of atherogenesis. Expression of decoy SRs retards early atherosclerotic lesion formation in experimental models (12). In advanced lesions, SR-associated signaling contributes to macrophage death and necrotic core formation (14), but this pro-atherogenic role of SRs is balanced by their ability to recognize and clear apoptotic cells in a nonphlogistic manner.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

IgE stimulates human and mouse arterial cell apoptosis and cytokine expression and promotes atherogenesis in Apoe–/– mice

et al. 2011

View full text Add to dashboard Cite

IgE has a key role in the pathogenesis of allergic responses through its ability to activate mast cells via the receptor FcεR1. In addition to mast cells, many cell types implicated in atherogenesis express FcεR1, but whether IgE has a role in this disease has not been determined. Here, we demonstrate that serum IgE levels are elevated in patients with myocardial infarction or unstable angina pectoris. We found that IgE and the FcεR1 subunit FcεR1α were present in human atherosclerotic lesions and that they localized particularly to macrophagerich areas. In mice, absence of FcεR1α reduced inflammation and apoptosis in atherosclerotic plaques and reduced the burden of disease. In cultured macrophages, the presence of TLR4 was required for FcεR1 activity. IgE stimulated the interaction between FcεR1 and TLR4, thereby inducing macrophage signal transduction, inflammatory molecule expression, and apoptosis. These IgE activities were reduced in the absence of FcεR1 or TLR4. Furthermore, IgE activated macrophages by enhancing Na + /H + exchanger 1 (NHE1) activity. Inactivation of NHE1 blocked IgE-induced macrophage production of inflammatory molecules and apoptosis. Cultured human aortic SMCs (HuSMCs) and ECs also exhibited IgE-induced signal transduction, cytokine expression, and apoptosis. In human atherosclerotic lesions, SMCs and ECs colocalized with IgE and TUNEL staining. This study reveals what we believe to be several previously unrecognized IgE activities that affect arterial cell biology and likely other IgE-associated pathologies in human diseases.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

IgE stimulates human and mouse arterial cell apoptosis and cytokine expression and promotes atherogenesis in Apoe–/– mice

et al. 2011

View full text Add to dashboard Cite

show abstract

“…18 Growth factors were secreted into the systemic circulation as detected by ELISA assays. Human VEGF-A, -B, -C, and -D were still detectable in the circulation 4 to 6 weeks after the gene transfer, although the peak expression was achieved 4 days after the gene transfer (Figure 1).…”

Section: Resultsmentioning

confidence: 99%

Gene Transfers of Vascular Endothelial Growth Factor-A, Vascular Endothelial Growth Factor-B, Vascular Endothelial Growth Factor-C, and Vascular Endothelial Growth Factor-D Have No Effects on Atherosclerosis in Hypercholesterolemic Low-Density Lipoprotein-Receptor/Apolipoprotein B48-Deficient Mice

et al. 2005

View full text Add to dashboard Cite

Background— The role of vascular endothelial growth factors (VEGFs) in large arteries has been proposed to be either vasculoprotective or proatherogenic. Because VEGF family members are used for human therapy, it is important to know whether they could enhance atherogenesis. We tested the effects of the members of the VEGF gene family on atherogenesis in LDL-receptor/apolipoprotein (apo) B48 double-knockout (LDLR/apoB48) mice using systemic adenoviral gene transfer. Methods and Results— Six groups of LDLR/apoB48-deficient mice (n=110) were kept 3 months on a Western-type diet. After 6 weeks of diet, mice were injected via tail vein with recombinant adenoviruses expressing VEGF-A, -B, -C, or -D or LacZ (1×10 9 PFU) or rhVEGF-A protein (2 μg/kg) and euthanized 6 weeks later. Also, older mice (n=36) were injected after 4 months on the diet and euthanized 6 weeks later (total time on the diet, 22 weeks) to evaluate the effects of gene transfers on the development of more mature lesions. Aortas were analyzed for the presence of macroscopic lesions, cross-sectional lesion areas, neovascularization, and cellular composition of the lesions. All groups had equivalent plasma cholesterol and triglyceride levels. Gene transfers with recombinant adenoviruses or administration of rhVEGF-A protein had no statistically significant effects on en face atherosclerotic lesions in the aorta, cross-sectional lesion area, neovascularization, or cellular composition of the lesions. Conclusions— This study shows no proatherogenic effects of adenovirus-mediated gene transfers of VEGF-A, -B, -C, or -D in the LDLR/apoB48-deficient hypercholesterolemic mice, in which lipoprotein profile and atherosclerosis closely resemble those in human disease.

show abstract

“…Adenoviral overexpression of the "decoy" soluble macrophage scavenger receptor AI that contains its extracellular portion inhibited foam cell formation in vitro 74 and reduced the atherosclerotic lesion area 6 weeks after gene transfer in LDL receptordeficient mice. 57 In addition, adeno-associated virus-based gene transfer of soluble macrophage scavenger receptor AI reduced aortic lesion area. 58 However, the effects on atherosclerotic lesions were relatively modest, which is likely to be caused by the limitations in gene transfer efficiency and the mild phenotype of LDL receptor-deficient mice.…”

Section: Soluble Scavenger Receptorsmentioning

confidence: 99%

“…Notable exceptions are the aforementioned genes as well as soluble macrophage scavenger receptor AI, which is produced by the liver and functions in the circulation. 26,47,49,57,58,62 The limited efficiency of current vectors can be circumvented with the use of localized, high-efficiency gene delivery methods. These can be applied to gene therapy for restenosis after angioplasty or coronary stenting, in which localized catheterbased delivery methods can be deployed, such as infusion/ perfusion and needle catheters for improved penetration of vectors into the intimal layer.…”

Section: Limited Transduction Of Cardiovascular Cellsmentioning

confidence: 99%

Antioxidant Gene Therapy for Cardiovascular Disease

et al. 2008

View full text Add to dashboard Cite

Abstract-Excessive production of reactive oxygen species has been implicated to play an important role in a number of cardiovascular pathologies, including hypertension, atherosclerosis, myocardial infarction, ischemia/reperfusion injury, and restenosis after angioplasty or venous bypass grafting. The formation of reactive oxygen species is balanced out by antioxidant defenses, and augmenting this defense by antioxidant therapies could therefore provide a potential means to treat conditions in which the formation of reactive oxygen species exceeds the capability of natural protective mechanisms. In this review, we summarize the studies in which antioxidant gene therapy has been used successfully to treat cardiovascular diseases. We also discuss the current limitations of antioxidant gene therapy and envision future therapeutic targets and methodological approaches for an improved outcome. (Circulation. 2008;117:2142-2150.)

show abstract

Adenovirus-mediated gene transfer of a secreted decoy human macrophage scavenger receptor (SR-AI) in LDL receptor knock-out mice

Cited by 33 publications

References 34 publications

IgE stimulates human and mouse arterial cell apoptosis and cytokine expression and promotes atherogenesis in Apoe–/– mice

IgE stimulates human and mouse arterial cell apoptosis and cytokine expression and promotes atherogenesis in Apoe–/– mice

Gene Transfers of Vascular Endothelial Growth Factor-A, Vascular Endothelial Growth Factor-B, Vascular Endothelial Growth Factor-C, and Vascular Endothelial Growth Factor-D Have No Effects on Atherosclerosis in Hypercholesterolemic Low-Density Lipoprotein-Receptor/Apolipoprotein B48-Deficient Mice

Antioxidant Gene Therapy for Cardiovascular Disease

Contact Info

Product

Resources

About