Hyperlipidemia in concert with hyperglycemia stimulates the proliferation of macrophages in atherosclerotic lesions - Potential role of glucose-oxidized LDL

被引:86
作者
Lamharzi, N
Renard, CB
Kramer, F
Pennathur, S
Heinecke, JW
Chait, A
Bornfeldt, KE
机构
[1] Univ Washington, Sch Med, Dept Pathol, Seattle, WA 98195 USA
[2] Univ Washington, Dept Med & Mol Biol, Seattle, WA 98195 USA
[3] Univ Washington, Dept Pharmacol, Seattle, WA 98195 USA
关键词
D O I
10.2337/diabetes.53.12.3217
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Hyperglycemia and hyperlipidemia are important risk factors for diabetes-accelerated atherosclerosis. Macrophage proliferation has been implicated in the progression of atherosclerosis. We therefore investigated the effects of hyperglycemia and hyperlipidemia on macrophage proliferation in murine atherosclerotic lesions and isolated, primary macrophages. Hyperglycemic LDL receptor-deficient mice that were fed a cholesterol-free diet for 12 weeks did not have elevated cholesterol levels compared with nondiabetic mice, and there was no evidence of increased macrophage proliferation in atherosclerotic lesions. Moreover, elevated glucose levels did not increase proliferation of isolated mouse peritoneal macrophages. In contrast, hyperglycemic LDL receptor-deficient mice that were fed a cholesterol-rich diet showed increased cholesterol levels concomitant with macrophage proliferation in atherosclerotic lesions. Glucose promoted lipid and protein oxidation of LDL in vitro. Glucose-oxidized LDL resulted in phosphorylation of extracellular signal-regulated kinase and protein kinase B/Akt and stimulated proliferation of isolated macrophages. The mitogenic effect of glucose-oxidized LDL was mediated by CD36 and by extracellular signal-regulated kinase activation induced by protein kinase C-dependent and phosphatidylinositol. 3-kinase-dependent pathways. Thus, hyperglycemia is not sufficient to stimulate macrophage proliferation in lesions of atherosclerosis or in isolated macrophages. A combination of hyperglycemia and hyperlipidemia, however, stimulates macrophage proliferation by a pathway that may involve the glucose-dependent oxidation of LDL.
引用
收藏
页码:3217 / 3225
页数:9
相关论文
共 46 条
[31]   Western-type diets induce insulin resistance and hyperinsulinemia in LDL receptor-deficient mice but do not increase aortic atherosclerosis compared with normoinsulinemic mice in which similar plasma cholesterol levels are achieved by a fructose-rich diet [J].
Merat, S ;
Casanada, F ;
Sutphin, M ;
Palinski, W ;
Reaven, PD .
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 1999, 19 (05) :1223-1230
[32]   Macrophage-specific p53 expression plays a crucial role in atherosclerosis development and plaque remodeling [J].
Merched, AJ ;
Williams, E ;
Chan, L .
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 2003, 23 (09) :1608-1614
[33]   A hydroxyl radical-like species oxidizes cynomolgus monkey artery wall proteins in early diabetic vascular disease [J].
Pennathur, S ;
Wagner, JD ;
Leeuwenburgh, C ;
Litwak, KN ;
Heinecke, JW .
JOURNAL OF CLINICAL INVESTIGATION, 2001, 107 (07) :853-860
[34]   Diabetes and diabetes-associated lipid abnormalities have distinct effects on initiation and progression of atherosclerotic lesions [J].
Renard, CB ;
Kramer, F ;
Johansson, F ;
Lamharzi, N ;
Tannock, LR ;
von Herrath, MG ;
Chait, A ;
Bornfeldt, KE .
JOURNAL OF CLINICAL INVESTIGATION, 2004, 114 (05) :659-668
[35]   MACROPHAGE AND SMOOTH-MUSCLE CELL-PROLIFERATION IN ATHEROSCLEROTIC LESIONS OF WHHL AND COMPARABLY HYPERCHOLESTEROLEMIC FAT-FED RABBITS [J].
ROSENFELD, ME ;
ROSS, R .
ARTERIOSCLEROSIS, 1990, 10 (05) :680-687
[36]  
ROSENFELD ME, 1992, AM J PATHOL, V140, P291
[37]  
Rudermann N. B., 1990, HYPERGLYCEMIA DIABET, P3
[38]  
SAKAI M, 1994, J BIOL CHEM, V269, P31430
[39]  
SAVENKOVA MI, 1994, J BIOL CHEM, V269, P20394
[40]   GLUCOSYLATION OF LOW-DENSITY LIPOPROTEINS TO AN EXTENT COMPARABLE TO THAT SEEN IN DIABETES SLOWS THEIR CATABOLISM [J].
STEINBRECHER, UP ;
WITZTUM, JL .
DIABETES, 1984, 33 (02) :130-134