Murine Models of Advanced Atherosclerosis

Rosenfeld, Michael E.; Schwartz, Stephen M.

doi:10.1002/9780470987575.ch7

Cited by 5 publications

(4 citation statements)

References 149 publications

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“…ApoE−/− mice have been widely used as an animal model of atherosclerosis and the murine carotid plaque induced by high-fat diet feeding and paravascular collar placement has been recognized as the most reproducible site for studies of advanced lesions [21] . Recently, we developed a new mouse model of vulnerable carotid plaque by using combinatorial stress stimulation and LPS injection and observed a high incidence of plaque disruption in these mice.…”

Section: Discussionmentioning

confidence: 99%

Local Gene Silencing of Monocyte Chemoattractant Protein-1 Prevents Vulnerable Plaque Disruption in Apolipoprotein E-Knockout Mice

Liu¹,

Zhang²,

Ding³

et al. 2012

PLoS ONE

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Monocyte chemoattractant protein-1 (MCP-1), a CC chemokine (CCL2), has been demonstrated to play important roles in atherosclerosis and becoming an important therapeutic target for atherosclerosis. The present study was undertaken to test the hypothesis that local RNAi of MCP-1 by site-specific delivery of adenovirus-mediated small hairpin RNA (shRNA) may enhance plaque stability and prevent plaque disruption in ApoE−/− mice. We designed an adenovirus-mediated shRNA against mouse MCP-1 (rAd5-MCP-1-shRNA). Male apolipoprotein E-knockout (ApoE−/−) mice (n = 120) were fed a high-fat diet and vulnerable plaques were induced by perivascular placement of constrictive collars around the carotid artery, intraperitoneal injection of lipopolysaccharide and stress stimulation. Mice were randomly divided into RNA interference (Ad-MCP-1i) group receiving local treatment of rAd5-MCP-1-shRNA suspension, Ad-EGFP group receiving treatment of rAd5-mediated negative shRNA and mock group receiving treatment of saline. Two weeks after treatment, plaque disruption rates were significantly lower in the Ad-MCP-1i group than in the Ad-EGFP group (13.3% vs. 60.0%, P = 0.01), and local MCP-1 expression was significantly inhibited in the Ad-MCP-1i group confirmed by immunostaining, qRT-PCR and western blot ( P <0.001). Compared with the Ad-EGFP group, carotid plaques in the Ad-MCP-1i group showed increased levels of collagen and smooth muscle cells, and decreased levels of lipid and macrophages. The expression of inflammatory cytokines and activities of matrix metalloproteinases (MMPs) were lower in the Ad-MCP-1i group than in the Ad-EGFP group. In conclusion, site-specific delivery of adenoviral-mediated shRNA targeting mouse MCP-1 downregulated MCP-1 expression, turned a vulnerable plaque into a more stable plaque phenotype and prevented plaque disruption. A marked suppression of the local inflammatory cytokine expression may be the central mechanism involved.

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Section: Discussionmentioning

confidence: 99%

Local Gene Silencing of Monocyte Chemoattractant Protein-1 Prevents Vulnerable Plaque Disruption in Apolipoprotein E-Knockout Mice

Liu¹,

Zhang²,

Ding³

et al. 2012

PLoS ONE

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“…These phenotype differences may explain why the carotid plaque area did not differ among our five groups of mice, whereas the aortic lesions may actually regress in TLR2 and TLR4 knockout mice [ 12 , 13 ]. Nonetheless, the carotid lesions in ApoE −/− mice resemble advanced human atherosclerosis and represent the most reproducible and reliable model for studies of vulnerable plaques [ 32 ]. Second, different amounts of TLR2 or TLR4 siRNA lentiviral vectors were given to different groups: 10 μl in the solo treated group and 5 μl of each vector in the combined treatment group.…”

Section: Discussionmentioning

confidence: 99%

Combinatorial interference of toll-like receptor 2 and 4 synergistically stabilizes atherosclerotic plaque in apolipoprotein E-knockout mice

Yang

Wang

et al. 2010

Journal of Cellular and Molecular Medicine

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To test the hypothesis that combinatorial interference of toll-like receptor 2 (TLR2) and TLR4 is superior to isolated interference of TLR2 or TLR4 in stabilizing atherosclerotic plaques, lentiviruses carrying small interfering RNA of TLR2 or TLR4 were constructed and proved efficacious for knocking down mRNA and protein expression of TLR2 or TLR4 significantly in vitro. One hundred and fifty apolipoprotein E−/− mice fed a high-fat diet were divided into the control, mock, TLR2i, TLR4i and TLR2 + 4i subgroups and a constrictive collar was placed around carotid artery of these mice to induce plaque formation. TLR2i and TLR4i viral suspension was transfected into carotid plaques, respectively, in TLR2i and TLR4i subgroups, or in combination in TLR2 + 4i subgroup. Four weeks after lentivirus transfection, mRNA and protein expression of TLR2 or TLR4 was attenuated markedly in carotid plaques, leading to reduced local inflammatory cytokine expression and plaque content of lipid and macrophages, increased plaque content of collagen and lowered plaque vulnerability index. Factorial ANOVA analysis revealed that there was a synergistic effect between TLR4i and TLR2i in stabilizing plaques. In conclusion, combinatorial interference of TLR2 and TLR4 reduces local inflammation and stabilizes plaques more effectively than interference of TLR2 or TLR4 alone.

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“…However, major differences have been described between the widely used apoE−/− mouse model and human atherosclerotic lesions (Bentzon et al, 2010) and the determination of similarities and differences between these species has been extensively addressed recently (Hansson et al, 2007; Schwartz et al, 2007; Jackson et al, 2007; Jackson, 2007; Falk et al, 2007; Rosenfeld et al, 2007; Rosenfeld et al, 2008; Bond et al, 2011). Specifically, distinct opinions have been expressed regarding the presence and characteristics of murine plaque rupture and the subsequent formation of thrombus.…”

Section: Introductionmentioning

confidence: 99%

Effects of mechanical properties and atherosclerotic artery size on biomechanical plaque disruption – Mouse vs. human

Riou¹,

Broisat²,

Ghezzi³

et al. 2014

Journal of Biomechanics

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Mouse models of atherosclerosis are extensively being used to study the mechanisms of atherosclerotic plaque development and the results are frequently extrapolated to humans. However, major differences have been described between murine and human atherosclerotic lesions and the determination of similarities and differences between these species has been largely addressed recently. This study takes over and extends previous studies performed by our group and related to the biomechanical characterization of both mouse and human atherosclerotic lesions. Its main objective was to determine the distribution and amplitude of mechanical stresses including peak cap stress (PCS) in aortic vessels from atherosclerotic, apoE−/− mice in order to evaluate whether such biomechanical data would be in accordance with the previously suggested lack of plaque rupture in this model. Successful finite element analysis was performed from the zero-stress configuration of aortic arch sections and mainly indicated (1) the modest role of atherosclerotic lesions in the observed increase in residual parietal stresses in apoE−/− mouse vessels and (2) the low amplitude of murine PCS as compared to humans. Overall, the results from the present study support the hypothesis that murine biomechanical properties and artery size confer less propensity to rupture for mouse lesions in comparison with those of humans.

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Murine Models of Advanced Atherosclerosis

Cited by 5 publications

References 149 publications

Local Gene Silencing of Monocyte Chemoattractant Protein-1 Prevents Vulnerable Plaque Disruption in Apolipoprotein E-Knockout Mice

Local Gene Silencing of Monocyte Chemoattractant Protein-1 Prevents Vulnerable Plaque Disruption in Apolipoprotein E-Knockout Mice

Combinatorial interference of toll-like receptor 2 and 4 synergistically stabilizes atherosclerotic plaque in apolipoprotein E-knockout mice

Effects of mechanical properties and atherosclerotic artery size on biomechanical plaque disruption – Mouse vs. human

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