Remnant Cholesterol Elicits Arterial Wall Inflammation and a Multilevel Cellular Immune Response in Humans
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Remnant Cholesterol Elicits Arterial Wall Inflammation and a Multilevel Cellular Immune Response in Humans. / Bernelot Moens, Sophie J; Verweij, Simone L; Schnitzler, Johan G; Stiekema, Lotte C A; Bos, Merijn; Langsted, Anne; Kuijk, Carlijn; Bekkering, Siroon; Voermans, Carlijn; Verberne, Hein J; Nordestgaard, Børge G; Stroes, Erik S G; Kroon, Jeffrey.
I: Arteriosclerosis, Thrombosis, and Vascular Biology, Bind 37, Nr. 5, 2017, s. 969-975.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Remnant Cholesterol Elicits Arterial Wall Inflammation and a Multilevel Cellular Immune Response in Humans
AU - Bernelot Moens, Sophie J
AU - Verweij, Simone L
AU - Schnitzler, Johan G
AU - Stiekema, Lotte C A
AU - Bos, Merijn
AU - Langsted, Anne
AU - Kuijk, Carlijn
AU - Bekkering, Siroon
AU - Voermans, Carlijn
AU - Verberne, Hein J
AU - Nordestgaard, Børge G
AU - Stroes, Erik S G
AU - Kroon, Jeffrey
N1 - © 2017 American Heart Association, Inc.
PY - 2017
Y1 - 2017
N2 - OBJECTIVE: Mendelian randomization studies revealed a causal role for remnant cholesterol in cardiovascular disease. Remnant particles accumulate in the arterial wall, potentially propagating local and systemic inflammation. We evaluated the impact of remnant cholesterol on arterial wall inflammation, circulating monocytes, and bone marrow in patients with familial dysbetalipoproteinemia (FD).APPROACH AND RESULTS: Arterial wall inflammation and bone marrow activity were measured using 18F-FDG PET/CT. Monocyte phenotype was assessed with flow cytometry. The correlation between remnant levels and hematopoietic activity was validated in the CGPS (Copenhagen General Population Study). We found a 1.2-fold increase of 18F-FDG uptake in the arterial wall in patients with FD (n=17, age 60±8 years, remnant cholesterol: 3.26 [2.07-5.71]) compared with controls (n=17, age 61±8 years, remnant cholesterol 0.29 [0.27-0.40]; P<0.001). Monocytes from patients with FD showed increased lipid accumulation (lipid-positive monocytes: Patients with FD 92% [86-95], controls 76% [66-81], P=0.001, with an increase in lipid droplets per monocyte), and a higher expression of surface integrins (CD11b, CD11c, and CD18). Patients with FD also exhibited monocytosis and leukocytosis, accompanied by a 1.2-fold increase of 18F-FDG uptake in bone marrow. In addition, we found a strong correlation between remnant levels and leukocyte counts in the CGPS (n=103 953, P for trend 5×10-276). In vitro experiments substantiated that remnant cholesterol accumulates in human hematopoietic stem and progenitor cells coinciding with myeloid skewing.CONCLUSIONS: Patients with FD have increased arterial wall and cellular inflammation. These findings imply an important inflammatory component to the atherogenicity of remnant cholesterol, contributing to the increased cardiovascular disease risk in patients with FD.
AB - OBJECTIVE: Mendelian randomization studies revealed a causal role for remnant cholesterol in cardiovascular disease. Remnant particles accumulate in the arterial wall, potentially propagating local and systemic inflammation. We evaluated the impact of remnant cholesterol on arterial wall inflammation, circulating monocytes, and bone marrow in patients with familial dysbetalipoproteinemia (FD).APPROACH AND RESULTS: Arterial wall inflammation and bone marrow activity were measured using 18F-FDG PET/CT. Monocyte phenotype was assessed with flow cytometry. The correlation between remnant levels and hematopoietic activity was validated in the CGPS (Copenhagen General Population Study). We found a 1.2-fold increase of 18F-FDG uptake in the arterial wall in patients with FD (n=17, age 60±8 years, remnant cholesterol: 3.26 [2.07-5.71]) compared with controls (n=17, age 61±8 years, remnant cholesterol 0.29 [0.27-0.40]; P<0.001). Monocytes from patients with FD showed increased lipid accumulation (lipid-positive monocytes: Patients with FD 92% [86-95], controls 76% [66-81], P=0.001, with an increase in lipid droplets per monocyte), and a higher expression of surface integrins (CD11b, CD11c, and CD18). Patients with FD also exhibited monocytosis and leukocytosis, accompanied by a 1.2-fold increase of 18F-FDG uptake in bone marrow. In addition, we found a strong correlation between remnant levels and leukocyte counts in the CGPS (n=103 953, P for trend 5×10-276). In vitro experiments substantiated that remnant cholesterol accumulates in human hematopoietic stem and progenitor cells coinciding with myeloid skewing.CONCLUSIONS: Patients with FD have increased arterial wall and cellular inflammation. These findings imply an important inflammatory component to the atherogenicity of remnant cholesterol, contributing to the increased cardiovascular disease risk in patients with FD.
KW - Aged
KW - Arteries
KW - Arteritis
KW - Bone Marrow Cells
KW - Case-Control Studies
KW - Cells, Cultured
KW - Cholesterol
KW - Denmark
KW - Female
KW - Fluorodeoxyglucose F18
KW - Hematopoietic Stem Cells
KW - Humans
KW - Hyperlipoproteinemia Type III
KW - Immunity, Cellular
KW - Integrins
KW - Lipoproteins
KW - Male
KW - Middle Aged
KW - Monocytes
KW - Phenotype
KW - Positron Emission Tomography Computed Tomography
KW - Radiopharmaceuticals
KW - Signal Transduction
KW - Triglycerides
KW - Journal Article
KW - Observational Study
KW - Validation Studies
U2 - 10.1161/ATVBAHA.116.308834
DO - 10.1161/ATVBAHA.116.308834
M3 - Journal article
C2 - 28336558
VL - 37
SP - 969
EP - 975
JO - Arteriosclerosis, Thrombosis, and Vascular Biology
JF - Arteriosclerosis, Thrombosis, and Vascular Biology
SN - 1079-5642
IS - 5
ER -
ID: 188363956