Macrophage retinoblastoma deficiency leads to enhanced atherosclerosis development in ApoE-deficient mice.
The cellular composition of an atherosclerotic lesion is determined by cell infiltration, proliferation, and apoptosis. The tumor suppressor gene retinoblastoma (Rb) has been shown to regulate both cell proliferation and cell death in many cell types. To study the role of macrophage Rb in the development of atherosclerosis, we used apoE-deficient mice with a macrophage-restricted deletion of Rb (Rb(del) mice) and control littermates (Rb(fl) mice). After 12 wk feeding a cholesterol-rich diet, the Rb(del) mice showed a 51% increase in atherosclerotic lesion area with a 39% increase in the relative number of advanced lesions. Atherosclerotic lesions showed a 13% decrease in relative macrophage area and a 46% increase in relative smooth muscle cell area, reflecting the more advanced state of the lesions. The increase in atherosclerosis was independent of in vitro macrophage modified lipoprotein uptake or cytokine production. Whereas macrophage-restricted Rb deletion did not affect lesional macrophage apoptosis, a clear 2.6-fold increase in lesional macrophage proliferation was observed. These studies demonstrate that macrophage Rb is a suppressing factor in the progression of atherosclerosis by reducing macrophage proliferation.
Department of General Internal Medicine, Leiden University Medical Center, c/o TNO Quality of Life, Gaubius Laboratory, Zernikedreef 9, P.O. Box 2215, Leiden 2301 CE, The Netherlands. lsmboesten@diac-leiden.nl
Lianne S M
LS
Boesten
A Susanne M
AS
Zadelaar
Anita
A
van Nieuwkoop
Lihui
L
Hu
Jos
J
Jonkers
Bob
B
van de Water
Marion J J
MJ
Gijbels
Ingeborg
I
van der Made
Menno P J
MP
de Winther
Louis M
LM
Havekes
Bart J M
BJ
van Vlijmen
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D050197:Atherosclerosis / Q000378:metabolism*; D016923:Cell Death; D049109:Cell Proliferation; D002784:Cholesterol / Q000097:blood; D017353:Gene Deletion; D005786:Gene Expression Regulation; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D016160:Retinoblastoma Protein / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*
D001057:Apolipoproteins E; D016160:Retinoblastoma Protein; D002784:Cholesterol