Macrophage p53 controls macrophage death in atherosclerotic lesions of apolipoprotein E deficient mice.
The cellular composition of atherosclerotic lesions is determined by many factors including cell infiltration, proliferation and cell death. Tumor suppressor gene p53 has been shown to regulate both cell proliferation and cell death in many cell types. In the present study, we investigated the role of macrophage p53 in the pathogenesis of early and advanced atherosclerosis. Using the Cre-loxP system we found that absence of macrophage p53 (p53(del)) strongly reduces apoptosis of macrophages both in early and advanced atherosclerotic lesions (-59% and -37%, respectively). Consequently, in advanced atherosclerosis, reduced apoptosis upon absence of macrophage p53, coincided with increased acellular necrotic core formation (+96%), increased macrophage content (+24%), and reduced cholesterol cleft accumulation (-41%). Proliferation was not affected by the absence of macrophage p53 in both early and advanced atherosclerosis. However, these significant changes in lesional cell death did not affect total lesion area in both early and advanced atherosclerosis, neither in the aortic root nor in the aortic arch and thoracic aorta in ApoE-deficient mice. Our data demonstrate that macrophage p53 is an important regulator of macrophage apoptosis, thereby preventing necrotic death of lesional macrophages. The regulation of this cell death balance directly affects lesion composition.
Boesten
Lianne S M
LS
Dept. of General Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands. l.s.m.boesten@lumc.nl
Zadelaar
A Susanne M
AS
van Nieuwkoop
Anita
A
Hu
Lihui
L
Teunisse
Amina F A S
AF
Jochemsen
Aart G
AG
Evers
Bastiaan
B
van de Water
Bob
B
Gijbels
Marion J J
MJ
van Vlijmen
Bart J M
BJ
Havekes
Louis M
LM
de Winther
Menno P J
MP
D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism / Q000473:pathology; D001018:Aortic Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D017209:Apoptosis; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D002784:Cholesterol / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009336:Necrosis; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D001057:Apolipoproteins E; D016159:Tumor Suppressor Protein p53; D003094:Collagen; D002784:Cholesterol