Reduced macrophage apoptosis is associated with accelerated atherosclerosis in low-density lipoprotein receptor-null mice.
OBJECTIVE
The majority of apoptotic cells in atherosclerotic lesions are macrophages. However, the pathogenic role of macrophage apoptosis in the development of atherosclerosis remains unclear. Elevated expression of Bax, one of the pivotal proapoptotic proteins of the Bcl-2 family, has been found in human atherosclerotic plaques. Activation of Bax also occurs in free cholesterol-loaded and oxysterol-treated mouse macrophages. In this study, we examined the effect of Bax deficiency in bone marrow-derived leukocytes on the development of atherosclerosis in low-density lipoprotein receptor-null (LDLR-/-) mice.


RESULTS
Fourteen 8-week-old male LDLR-/- mice were lethally irradiated and reconstituted with either wild-type (WT) C57BL6 or Bax-null (Bax-/-) bone marrow. Three weeks later, the mice were challenged with a Western diet for 10 weeks. No differences were found in the plasma cholesterol level between the WT and Bax-/- group. However, quantitation of cross sections from proximal aorta revealed a 49.2% increase (P=0.0259) in the mean lesion area of the Bax-/- group compared with the WT group. A 53% decrease in apoptotic macrophages in the Bax-/- group was found by TUNEL staining (P<0.05).


CONCLUSIONS
The reduction of apoptotic activity in macrophages stimulates atherosclerosis in LDLR-/- mice, which is consistent with the hypothesis that macrophage apoptosis suppresses the development of atherosclerosis.
Liu
June
J
Department of Biochemistry and Molecular Biology, East Tennessee State University, Johnson City, TN 37614, USA.
Thewke
Douglas P
DP
Su
Yan Ru
YR
Linton
MacRae F
MF
Fazio
Sergio
S
Sinensky
Michael S
MS
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001161:Arteriosclerosis / Q000378:metabolism* / Q000473:pathology; D001854:Bone Marrow Cells / Q000737:chemistry / Q000378:metabolism; D016026:Bone Marrow Transplantation; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D008074:Lipoproteins / Q000097:blood / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000494:pharmacology; D018655:Lymphocyte Count; D008214:Lymphocytes / Q000737:chemistry / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000172:deficiency; D011973:Receptors, LDL / Q000172:deficiency* / Q000502:physiology; D019311:Staurosporine / Q000494:pharmacology; D014280:Triglycerides / Q000097:blood / Q000378:metabolism; D051028:bcl-2-Associated X Protein
C494827:Bax protein, mouse; D008074:Lipoproteins; D008077:Lipoproteins, LDL; D019253:Proto-Oncogene Proteins c-bcl-2; D011973:Receptors, LDL; D014280:Triglycerides; D051028:bcl-2-Associated X Protein; C099252:oxidized low density lipoprotein; D002784:Cholesterol; D019311:Staurosporine