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Macrophage retinoblastoma deficiency leads to enhanced atherosclerosis development in ApoE-deficient mice

Lianne S. M. Boesten^*,,1, A. Susanne M. Zadelaar^,, Anita van Nieuwkoop^*,, Lihui Hu^*, Jos Jonkers^||, Bob van de Water^#, Marion J. J. Gijbels^**,, Ingeborg van der Made^**, Menno P. J. de Winther^**, Louis M. Havekes^*,, and Bart J. M. van Vlijmen

^* Department of General Internal Medicine,

Department of Cardiology,

Hemostasis and Thrombosis Research Center, Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands;

TNO-Quality of Life/Gaubius Laboratory, Leiden,

^|| The Netherlands Cancer Institute, Amsterdam, The Netherlands;

^# Div. of Toxicology, Leiden Amsterdam Center for Drug Research; and

^** Department of Molecular Genetics, Cardiovascular Research Institute Maastricht and

Department of Pathology, Maastricht University, Maastricht, The Netherlands

¹Correspondence: 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. E-mail: lsmboesten{at}diac-leiden.nl

ABSTRACT

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.—Boesten, L. S. M., Zadelaar, A. S. M., van Nieuwkoop, A., Hu, L., Jonkers, J., van de Water, B., Gijbels, M. J. J. van der Made, I., de Winther, M. P. J., Havekes, L. M., van Vlijmen, B. J. M. Macrophage retinoblastoma deficiency leads to enhanced atherosclerosis development in ApoE-deficient mice.

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