Apolipoprotein E and Atherosclerosis
http://www.100md.com
《动脉硬化血栓血管生物学》
From the Hyperlipidemia and Atherosclerosis Research Group, Clinical Research Institute of Montreal, Canada.
Correspondence to Jean Davignon, IRCM, 110 Pine Ave. West, Montreal, QC, H2W 1R7. E-mail jean.davignon@ircm.qc.ca
In humans, apolipoprotein E (apoE) is a polymorphic multifunctional protein.1 It is coded by three alleles (2, 3, 4) of a modulator gene (level, variability, and susceptibility gene) at the apoE locus on chromosome 19, determining six apoE genotypes and plasma phenotypes. Its pleiotropic effects are exerted on plasma lipoprotein metabolism, coagulation, oxidative processes, macrophage, glial cell and neuronal cell homeostasis, adrenal function, central nervous system physiology, inflammation, and cell proliferation.2,3 ApoE polymorphism modulates susceptibility to many diseases. It is, however, particularly notorious for its role in neurodegenerative disorders4 and atherosclerotic arterial disease.5,6 The 4 allele (phenotypes E4/4 and E4/3) that is associated with higher low density lipoprotein cholesterol (LDL-C) is considered proatherogenic, whereas the presence of the 2 allele (E3/2, E2/2), being associated with lower LDL-C levels, is deemed to have the opposite effect (although it may be associated with increased plasma triglycerides and lipoprotein remnants). This simple equation, however, is an oversimplification because these properties are subject to many environmental and genetic influences. ApoE has allele- and gender-dependent effects on reverse cholesterol transport, platelet aggregation, and oxidative processes that are likely to affect the overall atherogenic potential ascribed to modulation of lipoprotein metabolism.2,3,6 Notwithstanding the context dependency, a recent meta-analysis fully supports the presence of the 4 allele as a significant risk factor for coronary artery disease.7 Several mechanisms have been evoked to link apoE with atherosclerosis, but the relationship is not fully unraveled in humans. Nevertheless, some apoE mimetic peptides that promote LDL clearance are currently tested in animals for potential clinical applications.8,9
See page 436
The situation is relatively simpler in animals. The mouse model has been prominently useful to test mechanisms of atherogenesis and apoE-driven atherosclerosis modulation. The apoE (–/–) mouse has been used to this end in a wide variety of experiments to study the effect of diet and drugs, the role of inflammation, oxidation, immunomodulation, coagulation, and plaque composition, as well as atheroma progression and regression.6,10 The apoE knockout mouse reproduces many of the features of human apoE deficiency and develops spontaneous atherosclerosis which is enhanced by a high-cholesterol diet to the extent that the animal exhibits xanthomas. In recent years, this model has been used to determine the threshold of circulating apoE above which atherosclerosis develops and whether it is possible to distinguish between lipoprotein effects and effects related to other antiatherogenic properties of apoE.6 The heterozygous apoE (+/–) mouse does not spontaneously exhibit the lipid phenotype of the apoE knockout mouse but remains susceptible to lipoprotein abnormalities on an atherogenic diet. Very little circulating apoE is necessary to rescue the apoE–/– phenotype. After transplantation of bone marrow from normal mice into apoE-deficient mice, apoE is detected in serum, promotes clearance of lipoproteins, normalization of serum cholesterol concentrations, and is associated with virtually complete protection from diet-induced atherosclerosis.11 ApoE produced by macrophages, resulting in plasma levels 10% of normal (or 0.5 mg/dL), was sufficient to induce these changes. The source of circulating apoE is not a determinant factor. In apoE-null mice that express apoE in the adrenal glands at levels too low (<1% to 2% of wild type) to correct the hypercholesterolemia of their apoE–/– background, there is almost complete suppression of atherosclerotic lesion development.12 This implies that mechanisms other than improvement of the lipoprotein profile could account for the benefit of a small amount of circulating apoE but did not exclude effect of a change in a high turnover minor lipid component or modulation of other non-lipid abnormalities associated with apoE deficiency.13 Tangirala et al14,15 have shown that liver-specific adenoviral transfection of human apoE3 in LDL receptor–knockout mice markedly reduces atherosclerosis without improvement of the lipoprotein profile but with significant reduction of 8-iso-PGF2-VI levels in LDL, arterial wall, and urine. This was a major contribution in support of the antioxidant properties of apoE and their relevance to atherosclerosis. Recently, Wientgen et al16 have expressed apoE in the adrenals of apoE-deficient mice resulting in subphysiological plasma levels and submitted them to femoral artery injury. Even when concentrations of plasma apoE were as low as 0.1% of that of the wild type, apoE had the ability to inhibit neointimal formation, but plasma cholesterol concentration, though half that of the apoE-null littermates, was still 6x higher than that of the wild type. Multiple regression analysis indicated that apoE but not cholesterol levels were significantly associated with mean intima-to-media ratio reduction before and after adjusting for apoE, giving further credence to a non-lipid effect of apoE.
Elsewhere in this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Raffai et al17 have taken a new approach to isolate the apoE antiatherosclerotic effect from the lipid effect in a normolipidemic mouse with a very low expression of an E4-like murine apoE variant (Arg-61 apoE) resulting in apoE levels 2% to 5% of normal.18 This hypomorphic apoeh/hMxl-Cre mouse is normolipidemic on a chow diet but develops hypercholesterolemia on a high-fat diet which is reversed when the chow diet is resumed. Hypercholesterolemia was induced by a high-fat cholesterol-rich diet supplemented with cholic acid that resulted in severe aortic atherosclerosis after 18 weeks. The animals were then placed on a regressive chow diet for 16 weeks but half were induced to express physiological levels of plasma apoE while the others stayed with their original low ApoE expression. Although plasma cholesterol concentrations fell rapidly to similar levels with elimination of the aortic foam cell layer in both groups, physiological levels of apoE enhanced removal of neutral lipids from the fibrotic core in the induced animals. This is of importance, first because the authors demonstrate for the first time that physiological levels of apoE can induce atherosclerosis regression independently of lowering of plasma cholesterol. Second, in earlier experiments macrophage-derived apoE expression in apoE null mice has halted atherosclerosis progression but had not caused regression as in this study.6 Regression has been observed, however, with human apoE gene transfer in the apoE-deficient/nude mice19 and with other types of intervention.20,21 Third, this new model provides good opportunities for further research into the mechanisms responsible for a non-lipid antiatherogenic effect of apoE. Indeed the study raises a large number of questions that will need to be addressed. The regression was mainly ascribable to a neutral lipid loss in the fibrotic core; was this associated with reduction of the other markers of plaque instability, including macrophage and T-cell number, increase in collagen content, changes in matrix metalloproteinases or their inhibitors, or any other subtle modification of the fibrotic component? How much of this beneficial effect of apoE results from its antioxidant properties? Measurement of markers of oxidation need to be done in future experiments. The same applies to inflammatory markers, helper T cell balance (Th1/Th2 ratio), macrophage and endothelial cell activation, as well as to many other established pleiotropic effects of apoE that are likely to affect the atherogenic process. Does the interferon induced by the pI:pC injections to activate Cre impact on atherosclerotic changes? What is the effect of such low levels of apoE on endothelial dysfunction, an early injury conducive to atherogenesis? Finally, an important mechanism worth studying in this model is the role of the apoE-LRP interaction. There is recent evidence that LRP, its ligand apoE, and the platelet-derived growth factor receptor cooperate in the remodeling of the vascular wall and protect against atherosclerosis.22,23
Macrophage apoE secretion and antiatherogenic effects. ApoE secreted after differentiation of monocytes into macrophages is associated with expression of the scavenger receptor type A (SR-A) and modulated by positive (sterols) or negative (cytokines) factors. Secreted apoE forms lipoprotein particles that promote reverse cholesterol transport, some containing apoAI (pre–?-LpAI, -LpAI) whereas others are devoid of apoAI (LpE, pre–?-LpE, LpE). Cholesterol is thus mobilized from peripheral tissues towards the liver for excretion into the bile through the scavenger receptor B type 1 (SR-B1) or the remnant receptor (LDL-receptor related protein, LRP1). Obviously, the apoE generated that contributes to remnant formation comes in majority from the liver, not the macrophage. In addition, apoE has a putative antiatherosclerotic effect by its antioxidant, antiproliferative (smooth muscle cells, lymphocytes), antiinflammatory, antiplatelet, and nitric oxide (NO)–generating properties. Macrophages can promote formation of oxidized LDL (OxLDL); their uptake by macrophage OxLDL receptors (SR-A, LOX-1, CD36, and SR-PSOX) favors formation of foam cells. On the other hand, apoE inhibits LDL oxidation. This diagram is modified and updated from a previously-published drawing (Davignon J. Sang Thrombose et Vaisseaux. 2002;14:107–120).
References
Mahley RW. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science. 1988; 240: 622–630.
Davignon J. Apolipoprotéine E, une molécule polymorphe et pléiotrope - R?le dans l’athérosclérose et au-delà. Deuxième partie. Sang Thrombose et Vaisseaux. 2002; 14: 107–120.
Davignon J. Apolipoprotéine E, une molécule polymorphe et pléiotrope - R?le dans l’athérosclérose et au-delà. Première partie. Sang Thrombose et Vaisseaux. 2002; 14: 39–58.
Mahley RW, Nathan BP, Pitas RE. Apolipoprotein E: structure, function, and possible roles in Alzheimer’s disease. Ann N Y Acad Sci. 1996; 777: 139–145.
Davignon J, Gregg RE, Sing CF. Apolipoprotein E polymorphism and atherosclerosis. Arteriosclerosis. 1988; 8: 1–21.
Davignon J, Cohn JS, Mabile L, Bernier L. Apolipoprotein E and atherosclerosis: insight from animal and human studies. Clin Chim Acta. 1999; 286: 115–143.
Song YQ, Stampfer MJ, Liu SM. Meta-analysis: apolipoprotein E genotypes and risk for coronary heart disease. Ann Intern Med. 2004; 141: 137–147.
Nikoulin IR, Curtiss LK. An apolipoprotein E synthetic peptide targets to lipoproteins in plasma and mediates both cellular lipoprotein interactions in vitro and acute clearance of cholesterol-rich lipoproteins in vivo. J Clin Invest. 1998; 101: 223–234.
Garber DW, Handattu S, Aslan I, Datta G, Chaddha M, Anantharamaiah GM. Effect of an arginine-rich amphipathic helical peptide on plasma cholesterol in dyslipidemic mice. Atherosclerosis. 2003; 168: 229–237.
Ohashi R, Mu H, Yao QH, Chen CY. Cellular and molecular mechanisms of atherosclerosis with mouse models. Trends Cardiovasc Med. 2004; 14: 187–190.
Linton MF, Atkinson JB, Fazio S. Prevention of atherosclerosis in apolipoprotein E–deficient mice by bone marrow transplantation. Science. 1995; 267: 1034–1037.
Thorngate FE, Rudel LL, Walzem RL, Williams DL. Low levels of extrahepatic nonmacrophage apoE inhibit atherosclerosis without correcting hypercholesterolemia in ApoE-deficient mice. Arterioscler Thromb Vasc Biol. 2000; 20: 1939–1945.
Curtiss LK. ApoE in atherosclerosis: a protein with multiple hats. Arterioscler Thromb Vasc Biol. 2000; 20: 1852–1853.
Tsukamoto K, Tangirala RK, Chun S, Usher D, Pure E, Rader DJ. Hepatic expression of apolipoprotein E inhibits progression of atherosclerosis without reducing cholesterol levels in LDL receptor–deficient mice. Mol Ther. 2000; 1: 189–194.
Tangirala RK, Praticó D, FitzGerald GA, Chun S, Tsukamoto K, Maugeais C, Usher DC, Puré E, Rader DJ. Reduction of isoprostanes and regression of advanced atherosclerosis by apolipoprotein E. J Biol Chem. 2001; 276: 261–266.
Wientgen H, Thorngate FE, Omerhodzic S, Rolnitzky L, Fallon JT, Williams DL, Fisher EA. Subphysiologic apolipoprotein E (ApoE) plasma levels inhibit neointimal formation after arterial injury in ApoE-deficient mice. Arterioscler Thromb Vasc Biol. 2004; 24: 1460–1465.
Raffai RL, Loeb SM, Weisgraber KH. Apolipoprotein E promotes the regression of atherosclerosis independently of lowering plasma cholesterol levels. Arterioscler Thromb Vasc Biol. 2005: 25: 436–441.
Raffai RL, Weisgraber KH. Hypomorphic apolipoprotein E mice: a new model of conditional gene repair to examine apolipoprotein E-mediated metabolism. J Biol Chem. 2002; 277: 11064–11068.
Desurmont C, Caillaud JM, Emmanuel F, Benoit P, Fruchart JC, Castro G, Branellec D, Heard JM, Duverger N. Complete atherosclerosis regression after human ApoE gene transfer in ApoE-deficient/nude mice. Arterioscler Thromb Vasc Biol. 2000; 20: 435–442.
Ni WH, Tsuda Y, Sakono M, Imaizumi K. Dietary soy protein isolate, compared with casein, reduces atherosclerotic lesion area in apolipoprotein E-deficient mice. J Nutr. 1998; 128: 1884–1889.
Gijbels MJJ, Van der Cammen M, Van der Laan LJW, Emeis JJ, Havekes LM, Hofker MH, Kraal G. Progression and regression of atherosclerosis in APOE3-Leiden transgenic mice: an immunohistochemical study. Atherosclerosis. 1999; 143: 15–25.
Mazeika P, Nihoyannopoulos P, Joshi J, Oakley CM. Uses and limitations of high dose dipyridamole stress echocardiography for evaluation of coronary artery disease. Br Heart J. 1992; 67: 144–149.
Boucher P, Gotthardt M. LRP and PDGF signaling: A pathway to atherosclerosis. Trends Cardiovasc Med. 2004; 14: 55–60.(Jean Davignon)
Correspondence to Jean Davignon, IRCM, 110 Pine Ave. West, Montreal, QC, H2W 1R7. E-mail jean.davignon@ircm.qc.ca
In humans, apolipoprotein E (apoE) is a polymorphic multifunctional protein.1 It is coded by three alleles (2, 3, 4) of a modulator gene (level, variability, and susceptibility gene) at the apoE locus on chromosome 19, determining six apoE genotypes and plasma phenotypes. Its pleiotropic effects are exerted on plasma lipoprotein metabolism, coagulation, oxidative processes, macrophage, glial cell and neuronal cell homeostasis, adrenal function, central nervous system physiology, inflammation, and cell proliferation.2,3 ApoE polymorphism modulates susceptibility to many diseases. It is, however, particularly notorious for its role in neurodegenerative disorders4 and atherosclerotic arterial disease.5,6 The 4 allele (phenotypes E4/4 and E4/3) that is associated with higher low density lipoprotein cholesterol (LDL-C) is considered proatherogenic, whereas the presence of the 2 allele (E3/2, E2/2), being associated with lower LDL-C levels, is deemed to have the opposite effect (although it may be associated with increased plasma triglycerides and lipoprotein remnants). This simple equation, however, is an oversimplification because these properties are subject to many environmental and genetic influences. ApoE has allele- and gender-dependent effects on reverse cholesterol transport, platelet aggregation, and oxidative processes that are likely to affect the overall atherogenic potential ascribed to modulation of lipoprotein metabolism.2,3,6 Notwithstanding the context dependency, a recent meta-analysis fully supports the presence of the 4 allele as a significant risk factor for coronary artery disease.7 Several mechanisms have been evoked to link apoE with atherosclerosis, but the relationship is not fully unraveled in humans. Nevertheless, some apoE mimetic peptides that promote LDL clearance are currently tested in animals for potential clinical applications.8,9
See page 436
The situation is relatively simpler in animals. The mouse model has been prominently useful to test mechanisms of atherogenesis and apoE-driven atherosclerosis modulation. The apoE (–/–) mouse has been used to this end in a wide variety of experiments to study the effect of diet and drugs, the role of inflammation, oxidation, immunomodulation, coagulation, and plaque composition, as well as atheroma progression and regression.6,10 The apoE knockout mouse reproduces many of the features of human apoE deficiency and develops spontaneous atherosclerosis which is enhanced by a high-cholesterol diet to the extent that the animal exhibits xanthomas. In recent years, this model has been used to determine the threshold of circulating apoE above which atherosclerosis develops and whether it is possible to distinguish between lipoprotein effects and effects related to other antiatherogenic properties of apoE.6 The heterozygous apoE (+/–) mouse does not spontaneously exhibit the lipid phenotype of the apoE knockout mouse but remains susceptible to lipoprotein abnormalities on an atherogenic diet. Very little circulating apoE is necessary to rescue the apoE–/– phenotype. After transplantation of bone marrow from normal mice into apoE-deficient mice, apoE is detected in serum, promotes clearance of lipoproteins, normalization of serum cholesterol concentrations, and is associated with virtually complete protection from diet-induced atherosclerosis.11 ApoE produced by macrophages, resulting in plasma levels 10% of normal (or 0.5 mg/dL), was sufficient to induce these changes. The source of circulating apoE is not a determinant factor. In apoE-null mice that express apoE in the adrenal glands at levels too low (<1% to 2% of wild type) to correct the hypercholesterolemia of their apoE–/– background, there is almost complete suppression of atherosclerotic lesion development.12 This implies that mechanisms other than improvement of the lipoprotein profile could account for the benefit of a small amount of circulating apoE but did not exclude effect of a change in a high turnover minor lipid component or modulation of other non-lipid abnormalities associated with apoE deficiency.13 Tangirala et al14,15 have shown that liver-specific adenoviral transfection of human apoE3 in LDL receptor–knockout mice markedly reduces atherosclerosis without improvement of the lipoprotein profile but with significant reduction of 8-iso-PGF2-VI levels in LDL, arterial wall, and urine. This was a major contribution in support of the antioxidant properties of apoE and their relevance to atherosclerosis. Recently, Wientgen et al16 have expressed apoE in the adrenals of apoE-deficient mice resulting in subphysiological plasma levels and submitted them to femoral artery injury. Even when concentrations of plasma apoE were as low as 0.1% of that of the wild type, apoE had the ability to inhibit neointimal formation, but plasma cholesterol concentration, though half that of the apoE-null littermates, was still 6x higher than that of the wild type. Multiple regression analysis indicated that apoE but not cholesterol levels were significantly associated with mean intima-to-media ratio reduction before and after adjusting for apoE, giving further credence to a non-lipid effect of apoE.
Elsewhere in this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Raffai et al17 have taken a new approach to isolate the apoE antiatherosclerotic effect from the lipid effect in a normolipidemic mouse with a very low expression of an E4-like murine apoE variant (Arg-61 apoE) resulting in apoE levels 2% to 5% of normal.18 This hypomorphic apoeh/hMxl-Cre mouse is normolipidemic on a chow diet but develops hypercholesterolemia on a high-fat diet which is reversed when the chow diet is resumed. Hypercholesterolemia was induced by a high-fat cholesterol-rich diet supplemented with cholic acid that resulted in severe aortic atherosclerosis after 18 weeks. The animals were then placed on a regressive chow diet for 16 weeks but half were induced to express physiological levels of plasma apoE while the others stayed with their original low ApoE expression. Although plasma cholesterol concentrations fell rapidly to similar levels with elimination of the aortic foam cell layer in both groups, physiological levels of apoE enhanced removal of neutral lipids from the fibrotic core in the induced animals. This is of importance, first because the authors demonstrate for the first time that physiological levels of apoE can induce atherosclerosis regression independently of lowering of plasma cholesterol. Second, in earlier experiments macrophage-derived apoE expression in apoE null mice has halted atherosclerosis progression but had not caused regression as in this study.6 Regression has been observed, however, with human apoE gene transfer in the apoE-deficient/nude mice19 and with other types of intervention.20,21 Third, this new model provides good opportunities for further research into the mechanisms responsible for a non-lipid antiatherogenic effect of apoE. Indeed the study raises a large number of questions that will need to be addressed. The regression was mainly ascribable to a neutral lipid loss in the fibrotic core; was this associated with reduction of the other markers of plaque instability, including macrophage and T-cell number, increase in collagen content, changes in matrix metalloproteinases or their inhibitors, or any other subtle modification of the fibrotic component? How much of this beneficial effect of apoE results from its antioxidant properties? Measurement of markers of oxidation need to be done in future experiments. The same applies to inflammatory markers, helper T cell balance (Th1/Th2 ratio), macrophage and endothelial cell activation, as well as to many other established pleiotropic effects of apoE that are likely to affect the atherogenic process. Does the interferon induced by the pI:pC injections to activate Cre impact on atherosclerotic changes? What is the effect of such low levels of apoE on endothelial dysfunction, an early injury conducive to atherogenesis? Finally, an important mechanism worth studying in this model is the role of the apoE-LRP interaction. There is recent evidence that LRP, its ligand apoE, and the platelet-derived growth factor receptor cooperate in the remodeling of the vascular wall and protect against atherosclerosis.22,23
Macrophage apoE secretion and antiatherogenic effects. ApoE secreted after differentiation of monocytes into macrophages is associated with expression of the scavenger receptor type A (SR-A) and modulated by positive (sterols) or negative (cytokines) factors. Secreted apoE forms lipoprotein particles that promote reverse cholesterol transport, some containing apoAI (pre–?-LpAI, -LpAI) whereas others are devoid of apoAI (LpE, pre–?-LpE, LpE). Cholesterol is thus mobilized from peripheral tissues towards the liver for excretion into the bile through the scavenger receptor B type 1 (SR-B1) or the remnant receptor (LDL-receptor related protein, LRP1). Obviously, the apoE generated that contributes to remnant formation comes in majority from the liver, not the macrophage. In addition, apoE has a putative antiatherosclerotic effect by its antioxidant, antiproliferative (smooth muscle cells, lymphocytes), antiinflammatory, antiplatelet, and nitric oxide (NO)–generating properties. Macrophages can promote formation of oxidized LDL (OxLDL); their uptake by macrophage OxLDL receptors (SR-A, LOX-1, CD36, and SR-PSOX) favors formation of foam cells. On the other hand, apoE inhibits LDL oxidation. This diagram is modified and updated from a previously-published drawing (Davignon J. Sang Thrombose et Vaisseaux. 2002;14:107–120).
References
Mahley RW. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science. 1988; 240: 622–630.
Davignon J. Apolipoprotéine E, une molécule polymorphe et pléiotrope - R?le dans l’athérosclérose et au-delà. Deuxième partie. Sang Thrombose et Vaisseaux. 2002; 14: 107–120.
Davignon J. Apolipoprotéine E, une molécule polymorphe et pléiotrope - R?le dans l’athérosclérose et au-delà. Première partie. Sang Thrombose et Vaisseaux. 2002; 14: 39–58.
Mahley RW, Nathan BP, Pitas RE. Apolipoprotein E: structure, function, and possible roles in Alzheimer’s disease. Ann N Y Acad Sci. 1996; 777: 139–145.
Davignon J, Gregg RE, Sing CF. Apolipoprotein E polymorphism and atherosclerosis. Arteriosclerosis. 1988; 8: 1–21.
Davignon J, Cohn JS, Mabile L, Bernier L. Apolipoprotein E and atherosclerosis: insight from animal and human studies. Clin Chim Acta. 1999; 286: 115–143.
Song YQ, Stampfer MJ, Liu SM. Meta-analysis: apolipoprotein E genotypes and risk for coronary heart disease. Ann Intern Med. 2004; 141: 137–147.
Nikoulin IR, Curtiss LK. An apolipoprotein E synthetic peptide targets to lipoproteins in plasma and mediates both cellular lipoprotein interactions in vitro and acute clearance of cholesterol-rich lipoproteins in vivo. J Clin Invest. 1998; 101: 223–234.
Garber DW, Handattu S, Aslan I, Datta G, Chaddha M, Anantharamaiah GM. Effect of an arginine-rich amphipathic helical peptide on plasma cholesterol in dyslipidemic mice. Atherosclerosis. 2003; 168: 229–237.
Ohashi R, Mu H, Yao QH, Chen CY. Cellular and molecular mechanisms of atherosclerosis with mouse models. Trends Cardiovasc Med. 2004; 14: 187–190.
Linton MF, Atkinson JB, Fazio S. Prevention of atherosclerosis in apolipoprotein E–deficient mice by bone marrow transplantation. Science. 1995; 267: 1034–1037.
Thorngate FE, Rudel LL, Walzem RL, Williams DL. Low levels of extrahepatic nonmacrophage apoE inhibit atherosclerosis without correcting hypercholesterolemia in ApoE-deficient mice. Arterioscler Thromb Vasc Biol. 2000; 20: 1939–1945.
Curtiss LK. ApoE in atherosclerosis: a protein with multiple hats. Arterioscler Thromb Vasc Biol. 2000; 20: 1852–1853.
Tsukamoto K, Tangirala RK, Chun S, Usher D, Pure E, Rader DJ. Hepatic expression of apolipoprotein E inhibits progression of atherosclerosis without reducing cholesterol levels in LDL receptor–deficient mice. Mol Ther. 2000; 1: 189–194.
Tangirala RK, Praticó D, FitzGerald GA, Chun S, Tsukamoto K, Maugeais C, Usher DC, Puré E, Rader DJ. Reduction of isoprostanes and regression of advanced atherosclerosis by apolipoprotein E. J Biol Chem. 2001; 276: 261–266.
Wientgen H, Thorngate FE, Omerhodzic S, Rolnitzky L, Fallon JT, Williams DL, Fisher EA. Subphysiologic apolipoprotein E (ApoE) plasma levels inhibit neointimal formation after arterial injury in ApoE-deficient mice. Arterioscler Thromb Vasc Biol. 2004; 24: 1460–1465.
Raffai RL, Loeb SM, Weisgraber KH. Apolipoprotein E promotes the regression of atherosclerosis independently of lowering plasma cholesterol levels. Arterioscler Thromb Vasc Biol. 2005: 25: 436–441.
Raffai RL, Weisgraber KH. Hypomorphic apolipoprotein E mice: a new model of conditional gene repair to examine apolipoprotein E-mediated metabolism. J Biol Chem. 2002; 277: 11064–11068.
Desurmont C, Caillaud JM, Emmanuel F, Benoit P, Fruchart JC, Castro G, Branellec D, Heard JM, Duverger N. Complete atherosclerosis regression after human ApoE gene transfer in ApoE-deficient/nude mice. Arterioscler Thromb Vasc Biol. 2000; 20: 435–442.
Ni WH, Tsuda Y, Sakono M, Imaizumi K. Dietary soy protein isolate, compared with casein, reduces atherosclerotic lesion area in apolipoprotein E-deficient mice. J Nutr. 1998; 128: 1884–1889.
Gijbels MJJ, Van der Cammen M, Van der Laan LJW, Emeis JJ, Havekes LM, Hofker MH, Kraal G. Progression and regression of atherosclerosis in APOE3-Leiden transgenic mice: an immunohistochemical study. Atherosclerosis. 1999; 143: 15–25.
Mazeika P, Nihoyannopoulos P, Joshi J, Oakley CM. Uses and limitations of high dose dipyridamole stress echocardiography for evaluation of coronary artery disease. Br Heart J. 1992; 67: 144–149.
Boucher P, Gotthardt M. LRP and PDGF signaling: A pathway to atherosclerosis. Trends Cardiovasc Med. 2004; 14: 55–60.(Jean Davignon)