Dataset Information

Characterization of partial ligation-induced carotid atherosclerosis model using dual-modality molecular imaging in ApoE knock-out mice.

ABSTRACT:

Background

Recently, partial ligation of the common carotid artery (CCA) was reported to induce carotid atheromata rapidly in apolipoprotein-E knockout (ApoE(-/-)) mice. We investigated this new atherosclerosis model by using combined matrix-metalloproteinase (MMP) near-infrared fluorescent (NIRF) imaging and macrophage-tracking luciferase imaging.

Methodology and principal findings

Partial ligation of the left CCA was performed in 10-week-old ApoE(-/-) mice on a high fat diet (n=33); the internal and external carotid arteries and occipital artery were ligated, while the superior thyroid artery was left intact. Two thirds of the animals were treated with either LiCl or atorvastatin. At 1-week, Raw264.7 macrophages modified to express the enhanced firefly-luciferase reporter gene (10(7) Raw-luc cells) were injected intravenously. At 2-week, NIRF molecular imaging visualized strong MMP-2/9 activity in the ligated area of the left CCA as well as in the aortic arch. Left-to-right ratios of the NIRF signal intensities in the CCA had a decreasing gradient from the highest value in the upper-most ligated area to the lowest value in the lower-most region adjacent to the aortic arch. Luciferase imaging showed that most Raw-luc macrophages were recruited to the ligated area of the CCA rather than to the aortic arch, despite similarly strong MMP-2/9-related NIRF signal intensities in both areas. In addition, LiCl or atorvastatin could reduce MMP-2/9 activity in the aortic arch but not in the ligated area of the CCA.

Conclusions/significance

This is the first molecular imaging study to characterize the partial ligation-induced carotid atherosclerosis model. Molecularly divergent types of atherosclerosis were identified: conventional lipogenic atherosclerosis in the aorta vs. flow-related mechanical atherosclerosis in the partially ligated left system.

SUBMITTER: Shin IJ

PROVIDER: S-EPMC3772018 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Publications

Characterization of partial ligation-induced carotid atherosclerosis model using dual-modality molecular imaging in ApoE knock-out mice.

Shin Ik Jae IJ Shon Soo-Min SM Schellingerhout Dawid D Park Jin-Yong JY Kim Jeong-Yeon JY Lee Su Kyoung SK Lee Dong Kun DK Lee Ho Won HW Ahn Byeong-Cheol BC Kim Kwangmeyung K Kwon Ick Chan IC Kim Dong-Eog DE

PloS one 20130912 9

<h4>Background</h4>Recently, partial ligation of the common carotid artery (CCA) was reported to induce carotid atheromata rapidly in apolipoprotein-E knockout (ApoE(-/-)) mice. We investigated this new atherosclerosis model by using combined matrix-metalloproteinase (MMP) near-infrared fluorescent (NIRF) imaging and macrophage-tracking luciferase imaging.<h4>Methodology and principal findings</h4>Partial ligation of the left CCA was performed in 10-week-old ApoE(-/-) mice on a high fat diet (n= ...[more]

PMID: 24069197

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Project description:Studying the role of a particular gene in atherosclerosis typically requires a time-consuming and often difficult process of generating double knockouts or transgenics on ApoE-/- or LDL receptor (LDLR)-/- background. Recently, it was reported that adeno-associated-virus-8 (AAV8)-mediated overexpression of PCSK9 (AAV8-PCSK9) rapidly induced hyperlipidemia. However, using this method in C57BL6 wild-type (C57) mice, it took ~3 months to develop atherosclerosis. Our partial carotid ligation model is used to rapidly develop atherosclerosis by inducing disturbed flow in the left common carotid artery within 2 weeks in ApoE-/- or LDLR-/- mice. Here, we combined these two approaches to develop an accelerated model of atherosclerosis in C57 mice. C57 mice were injected with AAV9-PCSK9 or AAV9-luciferase (control) and high-fat diet was initiated. A week later, partial ligation was performed. Compared to the control, AAV-PCSK9 led to elevated serum PCSK9, hypercholesterolemia, and rapid atherosclerosis development within 3 weeks as determined by gross plaque imaging, and staining with Oil-Red-O, Movat's pentachrome, and CD45 antibody. These plaque lesions were comparable to the atherosclerotic lesions that have been previously observed in ApoE-/- or LDLR-/- mice that were subjected to partial carotid ligation and high-fat diet. Next, we tested whether our method can be utilized to rapidly determine the role of a particular gene in atherosclerosis. Using eNOS-/- and NOX1-/y mice on C57 background, we found that the eNOS-/- mice developed more advanced lesions, while the NOX1-/y mice developed less atherosclerotic lesions as compared to the C57 controls. These results are consistent with the previous findings using double knockouts (eNOS-/-_ApoE-/- and NOX1-/y_ApoE-/-). AAV9-PCSK9 injection followed by partial carotid ligation is an effective and time-saving approach to rapidly induce atherosclerosis. This accelerated model is well-suited to quickly determine the role of gene(s) interest without generating double or triple knockouts.

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Dataset Information

Characterization of partial ligation-induced carotid atherosclerosis model using dual-modality molecular imaging in ApoE knock-out mice.

Background

Methodology and principal findings

Conclusions/significance

Publications

Characterization of partial ligation-induced carotid atherosclerosis model using dual-modality molecular imaging in ApoE knock-out mice.

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