Dataset Information

Imaging Macrophage and Hematopoietic Progenitor Proliferation in Atherosclerosis.

ABSTRACT: Local plaque macrophage proliferation and monocyte production in hematopoietic organs promote progression of atherosclerosis. Therefore, noninvasive imaging of proliferation could serve as a biomarker and monitor therapeutic intervention.To explore (18)F-FLT positron emission tomography-computed tomography imaging of cell proliferation in atherosclerosis.(18)F-FLT positron emission tomography-computed tomography was performed in mice, rabbits, and humans with atherosclerosis. In apolipoprotein E knock out mice, increased (18)F-FLT signal was observed in atherosclerotic lesions, spleen, and bone marrow (standardized uptake values wild-type versus apolipoprotein E knock out mice, 0.05 ± 0.01 versus 0.17 ± 0.01, P<0.05 in aorta; 0.13 ± 0.01 versus 0.28 ± 0.02, P<0.05 in bone marrow; 0.06 ± 0.01 versus 0.22 ± 0.01, P<0.05 in spleen), corroborated by ex vivo scintillation counting and autoradiography. Flow cytometry confirmed significantly higher proliferation of macrophages in aortic lesions and hematopoietic stem and progenitor cells in the spleen and bone marrow in these mice. In addition, (18)F-FLT plaque signal correlated with the duration of high cholesterol diet (r(2)=0.33, P<0.05). Aortic (18)F-FLT uptake was reduced when cell proliferation was suppressed with fluorouracil in apolipoprotein E knock out mice (P<0.05). In rabbits, inflamed atherosclerotic vasculature with the highest (18)F-fluorodeoxyglucose uptake enriched (18)F-FLT. In patients with atherosclerosis, (18)F-FLT signal significantly increased in the inflamed carotid artery and in the aorta.(18)F-FLT positron emission tomography imaging may serve as an imaging biomarker for cell proliferation in plaque and hematopoietic activity in individuals with atherosclerosis.

SUBMITTER: Ye YX

PROVIDER: S-EPMC4619168 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Imaging Macrophage and Hematopoietic Progenitor Proliferation in Atherosclerosis.

Ye Yu-Xiang YX Calcagno Claudia C Binderup Tina T Courties Gabriel G Keliher Edmund J EJ Wojtkiewicz Gregory R GR Iwamoto Yoshiko Y Tang Jun J Pérez-Medina Carlos C Mani Venkatesh V Ishino Seigo S Johnbeck Camilla Bardram CB Knigge Ulrich U Fayad Zahi A ZA Libby Peter P Weissleder Ralph R Tawakol Ahmed A Dubey Shipra S Belanger Anthony P AP Di Carli Marcelo F MF Swirski Filip K FK Kjaer Andreas A Mulder Willem J M WJ Nahrendorf Matthias M

Circulation research 20150922 10

<h4>Rationale</h4>Local plaque macrophage proliferation and monocyte production in hematopoietic organs promote progression of atherosclerosis. Therefore, noninvasive imaging of proliferation could serve as a biomarker and monitor therapeutic intervention.<h4>Objective</h4>To explore (18)F-FLT positron emission tomography-computed tomography imaging of cell proliferation in atherosclerosis.<h4>Methods and results</h4>(18)F-FLT positron emission tomography-computed tomography was performed in mic ...[more]

PMID: 26394773

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Project description:Macrophages are key immune cells for the initiation and development of atherosclerotic lesions. However, the macrophage regulatory nodes that determine how lesions progress in response to dietary challenges are not fully understood. Liver X receptors (LXRs) are sterol-regulated transcription factors that play a central role in atherosclerosis by integrating cholesterol homeostasis and immunity. LXR pharmacological activation elicits a robust antiatherosclerotic transcriptional program in macrophages that can be affected by LXR? S196 phosphorylation in vitro. To investigate the impact of these transcriptional changes in atherosclerosis development, we have generated mice carrying a Ser-to-Ala mutation in myeloid cells in the LDL receptor (LDLR)-deficient atherosclerotic background (M-S196ALdlr-KO). M-S196ALdlr-KO mice fed a high-fat diet exhibit increased atherosclerotic plaque burden and lesions with smaller necrotic cores and thinner fibrous caps. These diet-induced phenotypic changes are consistent with a reprogramed macrophage transcriptome promoted by LXR?-S196A during atherosclerosis development. Remarkably, expression of several proliferation-promoting factors, including the protooncogene FoxM1 and its targets, is induced by LXR?-S196A. This is consistent with increased proliferation of plaque-resident cells in M-S196ALdlr-KO mice. Moreover, disrupted LXR? phosphorylation increases expression of phagocytic molecules, resulting in increased apoptotic cell removal by macrophages, explaining the reduced necrotic cores. Finally, the macrophage transcriptome promoted by LXR?-S196A under dietary perturbation is markedly distinct from that revealed by LXR ligand activation, highlighting the singularity of this posttranslational modification. Overall, our findings demonstrate that LXR? phosphorylation at S196 is an important determinant of atherosclerotic plaque development through selective changes in gene transcription that affect multiple pathways.

Dataset Information

Imaging Macrophage and Hematopoietic Progenitor Proliferation in Atherosclerosis.

Publications

Imaging Macrophage and Hematopoietic Progenitor Proliferation in Atherosclerosis.

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