Imaging Macrophage and Hematopoietic Progenitor Proliferation in Atherosclerosis

Yu-Xiang Ye; Claudia Calcagno; Tina Binderup; Gabriel Courties; Edmund J Keliher; Gregory R Wojtkiewicz; Yoshiko Iwamoto; Jun Tang; Carlos Pérez-Medina; Venkatesh Mani; Seigo Ishino; Camilla Bardram Johnbeck; Ulrich Knigge; Zahi A Fayad; Peter Libby; Ralph Weissleder; Ahmed Tawakol; Shipra Dubey; Anthony P Belanger; Marcelo F Di Carli; Filip K Swirski; Andreas Kjaer; Willem J M Mulder; Matthias Nahrendorf

doi:10.1161/circresaha.115.307024

Imaging Macrophage and Hematopoietic Progenitor Proliferation in Atherosclerosis

Yu-Xiang Ye, Claudia Calcagno, Tina Binderup, Gabriel Courties, Edmund J Keliher, Gregory R Wojtkiewicz, Yoshiko Iwamoto, Jun Tang, Carlos Pérez-Medina, Venkatesh Mani, Seigo Ishino, Camilla Bardram Johnbeck, Ulrich Knigge, Zahi A Fayad, Peter Libby, Ralph Weissleder, Ahmed Tawakol, Shipra Dubey, Anthony P Belanger, Marcelo F Di CarliFilip K Swirski, Andreas Kjaer, Willem J M Mulder, Matthias Nahrendorf

44 Citations (Scopus)

Abstract

Rationale: 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. Objective: To explore ¹8F-FLT positron emission tomography-computed tomography imaging of cell proliferation in atherosclerosis. Methods and Results: ¹8F-FLT positron emission tomography-computed tomography was performed in mice, rabbits, and humans with atherosclerosis. In apolipoprotein E knock out mice, increased ¹8F-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, ¹8F-FLT plaque signal correlated with the duration of high cholesterol diet (r²=0.33, P<0.05). Aortic ¹8F-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 ¹8F-fluorodeoxyglucose uptake enriched ¹8F-FLT. In patients with atherosclerosis, ¹8F-FLT signal significantly increased in the inflamed carotid artery and in the aorta. Conclusions: ¹8F-FLT positron emission tomography imaging may serve as an imaging biomarker for cell proliferation in plaque and hematopoietic activity in individuals with atherosclerosis.

Original language	English
Journal	Circulation Research
Volume	117
Issue number	10
Pages (from-to)	835-45
Number of pages	11
ISSN	0009-7330
DOIs	https://doi.org/10.1161/circresaha.115.307024
Publication status	Published - 23 Oct 2015

Keywords

Animals
Aorta, Thoracic
Aortic Diseases
Apolipoproteins E
Atherosclerosis
Bone Marrow
Carotid Artery Diseases
Cell Proliferation
Cholesterol, Dietary
Dideoxynucleosides
Diet, High-Fat
Disease Models, Animal
Female
Fluorodeoxyglucose F18
Hematopoietic Stem Cells
Humans
Macrophages
Male
Mice, Inbred C57BL
Mice, Knockout
Multimodal Imaging
Plaque, Atherosclerotic
Positron-Emission Tomography
Predictive Value of Tests
Rabbits
Radiopharmaceuticals
Retrospective Studies
Spleen
Time Factors
Tomography, X-Ray Computed

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CIRCRESAHA.115.307024Final published version, 8.07 MB

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Ye, Y-X., Calcagno, C., Binderup, T., Courties, G., Keliher, E. J., Wojtkiewicz, G. R., Iwamoto, Y., Tang, J., Pérez-Medina, C., Mani, V., Ishino, S., Johnbeck, C. B., Knigge, U., Fayad, Z. A., Libby, P., Weissleder, R., Tawakol, A., Dubey, S., Belanger, A. P., ... Nahrendorf, M. (2015). Imaging Macrophage and Hematopoietic Progenitor Proliferation in Atherosclerosis. Circulation Research, 117(10), 835-45. https://doi.org/10.1161/circresaha.115.307024

Ye, Y-X, Calcagno, C, Binderup, T, Courties, G, Keliher, EJ, Wojtkiewicz, GR, Iwamoto, Y, Tang, J, Pérez-Medina, C, Mani, V, Ishino, S, Johnbeck, CB, Knigge, U, Fayad, ZA, Libby, P, Weissleder, R, Tawakol, A, Dubey, S, Belanger, AP, Di Carli, MF, Swirski, FK, Kjaer, A, Mulder, WJM & Nahrendorf, M 2015, 'Imaging Macrophage and Hematopoietic Progenitor Proliferation in Atherosclerosis', Circulation Research, vol. 117, no. 10, pp. 835-45. https://doi.org/10.1161/circresaha.115.307024

@article{77f2319958a94d038af1018c4b2e97bc,

title = "Imaging Macrophage and Hematopoietic Progenitor Proliferation in Atherosclerosis",

abstract = "Rationale: 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. Objective: To explore 18F-FLT positron emission tomography-computed tomography imaging of cell proliferation in atherosclerosis. Methods and Results: 18F-FLT positron emission tomography-computed tomography was performed in mice, rabbits, and humans with atherosclerosis. In apolipoprotein E knock out mice, increased 18F-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, 18F-FLT plaque signal correlated with the duration of high cholesterol diet (r2=0.33, P<0.05). Aortic 18F-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 18F-fluorodeoxyglucose uptake enriched 18F-FLT. In patients with atherosclerosis, 18F-FLT signal significantly increased in the inflamed carotid artery and in the aorta. Conclusions: 18F-FLT positron emission tomography imaging may serve as an imaging biomarker for cell proliferation in plaque and hematopoietic activity in individuals with atherosclerosis.",

keywords = "Animals, Aorta, Thoracic, Aortic Diseases, Apolipoproteins E, Atherosclerosis, Bone Marrow, Carotid Artery Diseases, Cell Proliferation, Cholesterol, Dietary, Dideoxynucleosides, Diet, High-Fat, Disease Models, Animal, Female, Fluorodeoxyglucose F18, Hematopoietic Stem Cells, Humans, Macrophages, Male, Mice, Inbred C57BL, Mice, Knockout, Multimodal Imaging, Plaque, Atherosclerotic, Positron-Emission Tomography, Predictive Value of Tests, Rabbits, Radiopharmaceuticals, Retrospective Studies, Spleen, Time Factors, Tomography, X-Ray Computed",

author = "Yu-Xiang Ye and Claudia Calcagno and Tina Binderup and Gabriel Courties and Keliher, {Edmund J} and Wojtkiewicz, {Gregory R} and Yoshiko Iwamoto and Jun Tang and Carlos P{\'e}rez-Medina and Venkatesh Mani and Seigo Ishino and Johnbeck, {Camilla Bardram} and Ulrich Knigge and Fayad, {Zahi A} and Peter Libby and Ralph Weissleder and Ahmed Tawakol and Shipra Dubey and Belanger, {Anthony P} and {Di Carli}, {Marcelo F} and Swirski, {Filip K} and Andreas Kjaer and Mulder, {Willem J M} and Matthias Nahrendorf",

note = "{\textcopyright} 2015 American Heart Association, Inc.",

year = "2015",

month = oct,

day = "23",

doi = "10.1161/circresaha.115.307024",

language = "English",

volume = "117",

pages = "835--45",

journal = "Circulation Research",

issn = "0009-7330",

publisher = "AHA/ASA",

number = "10",

}

TY - JOUR

T1 - Imaging Macrophage and Hematopoietic Progenitor Proliferation in Atherosclerosis

AU - Ye, Yu-Xiang

AU - Calcagno, Claudia

AU - Binderup, Tina

AU - Courties, Gabriel

AU - Keliher, Edmund J

AU - Wojtkiewicz, Gregory R

AU - Iwamoto, Yoshiko

AU - Tang, Jun

AU - Pérez-Medina, Carlos

AU - Mani, Venkatesh

AU - Ishino, Seigo

AU - Johnbeck, Camilla Bardram

AU - Knigge, Ulrich

AU - Fayad, Zahi A

AU - Libby, Peter

AU - Weissleder, Ralph

AU - Tawakol, Ahmed

AU - Dubey, Shipra

AU - Belanger, Anthony P

AU - Di Carli, Marcelo F

AU - Swirski, Filip K

AU - Kjaer, Andreas

AU - Mulder, Willem J M

AU - Nahrendorf, Matthias

PY - 2015/10/23

Y1 - 2015/10/23

N2 - Rationale: 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. Objective: To explore 18F-FLT positron emission tomography-computed tomography imaging of cell proliferation in atherosclerosis. Methods and Results: 18F-FLT positron emission tomography-computed tomography was performed in mice, rabbits, and humans with atherosclerosis. In apolipoprotein E knock out mice, increased 18F-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, 18F-FLT plaque signal correlated with the duration of high cholesterol diet (r2=0.33, P<0.05). Aortic 18F-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 18F-fluorodeoxyglucose uptake enriched 18F-FLT. In patients with atherosclerosis, 18F-FLT signal significantly increased in the inflamed carotid artery and in the aorta. Conclusions: 18F-FLT positron emission tomography imaging may serve as an imaging biomarker for cell proliferation in plaque and hematopoietic activity in individuals with atherosclerosis.

AB - Rationale: 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. Objective: To explore 18F-FLT positron emission tomography-computed tomography imaging of cell proliferation in atherosclerosis. Methods and Results: 18F-FLT positron emission tomography-computed tomography was performed in mice, rabbits, and humans with atherosclerosis. In apolipoprotein E knock out mice, increased 18F-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, 18F-FLT plaque signal correlated with the duration of high cholesterol diet (r2=0.33, P<0.05). Aortic 18F-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 18F-fluorodeoxyglucose uptake enriched 18F-FLT. In patients with atherosclerosis, 18F-FLT signal significantly increased in the inflamed carotid artery and in the aorta. Conclusions: 18F-FLT positron emission tomography imaging may serve as an imaging biomarker for cell proliferation in plaque and hematopoietic activity in individuals with atherosclerosis.

KW - Animals

KW - Aorta, Thoracic

KW - Aortic Diseases

KW - Apolipoproteins E

KW - Atherosclerosis

KW - Bone Marrow

KW - Carotid Artery Diseases

KW - Cell Proliferation

KW - Cholesterol, Dietary

KW - Dideoxynucleosides

KW - Diet, High-Fat

KW - Disease Models, Animal

KW - Female

KW - Fluorodeoxyglucose F18

KW - Hematopoietic Stem Cells

KW - Humans

KW - Macrophages

KW - Male

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Multimodal Imaging

KW - Plaque, Atherosclerotic

KW - Positron-Emission Tomography

KW - Predictive Value of Tests

KW - Rabbits

KW - Radiopharmaceuticals

KW - Retrospective Studies

KW - Spleen

KW - Time Factors

KW - Tomography, X-Ray Computed

U2 - 10.1161/circresaha.115.307024

DO - 10.1161/circresaha.115.307024

M3 - Journal article

C2 - 26394773

SN - 0009-7330

VL - 117

SP - 835

EP - 845

JO - Circulation Research

JF - Circulation Research

IS - 10

ER -

Imaging Macrophage and Hematopoietic Progenitor Proliferation in Atherosclerosis

Abstract

Keywords

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