RESUMEN
Studies in vitro have shown that copper-zinc superoxide dismutase (CuZn-SOD) inhibits a number of events putatively involved in atherogenesis, including cell-mediated oxidation of LDL. To investigate whether increased activity of CuZn-SOD reduces atherogenesis in vivo, we examined diet-induced fatty streak formation in CuZn-SOD transgenic mice (n = 24) as compared with their nontransgenic littermates (n = 28). Transgenic animals were originally created by introduction of an EcoRI-BamHI human genomic DNA fragment containing the CuZn-SOD gene and its regulatory elements into B6SJL zygotes. For the current studies, the transgene was bred for 12 generations into the atherosclerosis-susceptible C57BL/6 background. Animals were fed atherogenic diets (15% fat, 1.25% cholesterol, 0.5% Na cholate) starting at 100 weeks of age and extending for 18 weeks. At the end of the diet period, aortic SOD activity was two-fold higher in transgenics than nontransgenics (mean +/- SE: 46.7 +/- 5.8 versus 20.1 +/- 2.4 units/mg of protein, P < .001). Levels of protein-bound amino acid oxidation products (meta-, ortho-, and dityrosine) were either similar or lower in aorta and heart from transgenics as compared with nontransgenics, suggesting that amplification of CuZn-SOD activity above the normal complement had modest inhibitory effects on basal oxidative stress in these tissues. CuZn-SOD overexpression did not reduce the extent of lesion development as analyzed by quantitative lipid staining of serial sections of the proximal aorta; mean lesion areas (+/- SE) were 997 +/- 478 and 943 +/- 221 mu 2 in transgenics and nontransgenics, respectively. Notably, the range of values for lesion area was 2.2-fold greater in transgenics (0-8403 versus 0-3868 mu 2 in nontransgenics). Moreover, within this group, lesion area showed a significant positive correlation with SOD activity (r = .611, P < .03). These results do not support an antiatherogenic effect of Cu-Zn-SOD over expression and raise the possibility that high tissue SOD activity may potentiate atherogenesis in fat-fed atherosclerosis-susceptible mice [corrected].
Asunto(s)
Arteriosclerosis/etiología , Grasas de la Dieta/administración & dosificación , Superóxido Dismutasa/metabolismo , Aminoácidos/metabolismo , Animales , Aorta/metabolismo , Aorta/patología , Arteriosclerosis/metabolismo , Arteriosclerosis/patología , Colesterol/sangre , HDL-Colesterol/sangre , Grasas de la Dieta/farmacología , Femenino , Humanos , Lipoproteínas/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos/genética , Miocardio/metabolismo , Oxidación-Reducción , Superóxido Dismutasa/genéticaRESUMEN
Elevated levels of apolipoprotein[a] (apo[a]) and apolipoprotein A-I (apoA-I) are associated, respectively, with increased and decreased atherosclerosis risk, in both humans and transgenic mice. To investigate the interactions of these two important lipid-associated proteins, we assessed the effect of expression of human apoA-I and apo[a] transgenes, both singularly and together, on murine atherogenesis. Mice expressing the apo[a] transgene have a lipoprotein profile similar to nontransgenic controls, yet have significantly increased susceptibility to diet-induced atherosclerosis. Compared to mice expressing only the apo[a] transgene, mice expressing both apo[a] and apoA-I transgenes have twofold greater high density lipoprotein (HDL) concentrations and approximately a 20-fold decrease in development of early atherosclerotic lesions. The finding of decreased atherosclerosis in the setting of elevated apo[a] and apoA-I suggests that elevations of apoA-I and HDL have a dominant effect in reducing atherosclerosis susceptibility in various settings, including those not associated with alterations of plasma lipids.
Asunto(s)
Apolipoproteína A-I/genética , Apolipoproteínas/genética , Arteriosclerosis/prevención & control , Expresión Génica , Lipoproteína(a) , Animales , Apolipoproteína A-I/fisiología , Apolipoproteínas/fisiología , Apoproteína(a) , Arteriosclerosis/etiología , Colesterol/sangre , HDL-Colesterol/sangre , Dieta , Humanos , Lipoproteínas/sangre , Ratones , Ratones Endogámicos C57BL , Ratones TransgénicosRESUMEN
Apolipoprotein (apo) E is a ligand for lipoprotein receptors and mediates the cellular uptake of several different lipoproteins. Human apoE occurs in three allelic forms designated E2, E3, and E4. The E2 isoform is associated with changes in lipoprotein metabolism, and the E4 isoform is associated with Alzheimer's disease and an increased risk of coronary heart disease. In this study transgenic mice were generated to assess the effect of a sustained increase in plasma apoE4 concentration. The transgenic animals had three- to sixfold increases in total plasma apoE, associated primarily with the non-high-density lipoprotein (HDL) fractions of plasma lipoproteins. In response to an atherogenic diet the transgenic mice developed hypercholesterolemia similar to that in nontransgenic mice but did not experience the decrease in HDL cholesterol normally observed in this strain of C57BL/6 mice. The rate of plasma clearance of a lipid emulsion mimicking lymph chylomicrons was measured in transgenic mice expressing the human apoE4 gene and compared with the clearance rate in nontransgenic control animals. In animals fed a low-fat diet the emulsion lipids were cleared significantly more rapidly from the plasma of transgenic than control mice. In animals adapted to a high-fat diet, the clearance of chylomicron remnants was slowed markedly in both transgenic and control mice and was not significantly accelerated in transgenic compared with control animals. We also investigated the effect of increasing the plasma concentration of apoE4 on the progression of atherosclerotic heart disease.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Apolipoproteínas E/farmacología , Arteriosclerosis/etiología , Quilomicrones/metabolismo , Metabolismo de los Lípidos , Animales , Apolipoproteína E4 , Apolipoproteínas/sangre , Apolipoproteínas E/genética , Arteriosclerosis/genética , Arteriosclerosis/patología , Emulsiones , Humanos , Lipasa/metabolismo , Lípidos/sangre , Lipoproteínas/sangre , Ratones , Ratones Transgénicos , Receptores de LDL/metabolismoRESUMEN
High-density lipoprotein (HDL) contains two major proteins, apolipoprotein A-I (apoA-I) and apolipoprotein A-II (apoA-II), comprising about 70% and 20% of the total HDL protein mass, respectively. HDL exists in human plasma in two main forms, one containing apoA-I with apoA-II (AI/AII-HDL) and another containing apoA-I without apoA-II (AI-HDL). A strong inverse relationship exists between total plasma HDL concentration and atherosclerosis, but the results of studies examining the relationship between AI-HDL and AI/AII-HDL and atherosclerosis have been conflicting. To determine whether these two HDL populations have different effects on atherogenesis, human apoA-I (AI) and human apoA-I and apoA-II (AI/AII) transgenic mice were produced in an atherosclerosis-susceptible strain. Following an atherogenic diet, despite similar total cholesterol and HDL cholesterol concentrations, the area of atherogenic lesions in the AI/AII mice was 15-fold greater than in the AI animals. These studies show that the protein composition of HDL significantly affects its role in atherogenesis and that AI-HDL is more antiatherogenic than AI/AII-HDL.
Asunto(s)
Apolipoproteína A-II/fisiología , Apolipoproteína A-I/fisiología , Arteriosclerosis/etiología , Lipoproteínas HDL/química , Lipoproteínas HDL/fisiología , Animales , Susceptibilidad a Enfermedades , Femenino , Humanos , Lipoproteínas HDL/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones TransgénicosRESUMEN
Elevated plasma levels of the lipoprotein Lp(a) are associated with increased risk for atherosclerosis and its manifestations, myocardial infarction, stroke and restenosis (for reviews, see refs 1-3). Lp(a) differs from low-density lipoprotein by the addition of the glycoprotein apolipoprotein(a), a homologue of plasminogen that contains many tandemly repeated units which resemble the fourth kringle domain of plasminogen, and single homologues of its kringle-5 and protease domain. As plasma Lp(a) concentration is strongly influenced by heritable factors and is refractory to most drug and dietary manipulation, the effects of modulating it are difficult to mimic experimentally. In addition, the absence of apolipoprotein(a) from virtually all species other than primates precludes the use of convenient animal models. Here we show that transgenic mice expressing human apolipoprotein(a) are more susceptible than control mice to the development of lipid-staining lesions in the aorta, and that apolipoprotein(a) co-localizes with lipid deposition in the artery walls.
Asunto(s)
Apolipoproteínas/genética , Arteriosclerosis/genética , Lipoproteína(a) , Animales , Aorta/metabolismo , Aorta/patología , Apolipoproteínas/análisis , Apolipoproteínas/metabolismo , Apoproteína(a) , Arteriosclerosis/metabolismo , Arteriosclerosis/patología , ADN/genética , Dieta Aterogénica , Humanos , Immunoblotting , Ratones , Ratones Transgénicos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Miocardio/metabolismo , Miocardio/patología , Valores de ReferenciaRESUMEN
apoE-deficient mice have been created by homologous recombination in ES cells. On a low fat, low cholesterol chow diet these animals have plasma cholesterol levels of 494 mg/dl compared with 60 mg/dl in control animals, and when challenged with a high fat Western-type diet, these animals have plasma cholesterol levels of 1821 mg/dl compared with 132 mg/dl in controls. This marked hypercholesterolemia is primarily due to elevated levels of very low and intermediate density lipoproteins. At 10 weeks of age, apoE-deficient mice have already developed atherosclerotic lesions in the aorta and coronary and pulmonary arteries. apoE-deficient mice are a promising small animal model to help understand the role of apoE in vivo and the genetic and environmental determinants of atherosclerosis.
Asunto(s)
Apolipoproteínas E/deficiencia , Arteriosclerosis/genética , Hipercolesterolemia/genética , Animales , Aorta/patología , Arteriosclerosis/patología , Colesterol/sangre , Vasos Coronarios/patología , Modelos Animales de Enfermedad , Hipercolesterolemia/patología , Lipoproteínas/sangre , Lipoproteínas IDL , Lipoproteínas VLDL/sangre , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos , Arteria Pulmonar/patología , Células MadreRESUMEN
Epidemiological surveys have identified a strong inverse relationship between the amount in the plasma of high density lipoproteins (HDL), apolipoprotein AI (ApoA-I), the major protein component of HDL, and the risk for atherosclerosis in humans. It is not known if this relationship arises from a direct antiatherogenic effect of these plasma components or if it is the result of other factors also associated with increases in ApoA-I and HDL levels. Because some strains of mice are susceptible to diet-induced formation of preatherosclerotic fatty streak lesions, and because of available techniques for the genetic manipulation of this organism, the murine system offers a unique setting in which to investigate the process of early atherogenesis. To test the hypothesis that induction of a high plasma concentration of ApoA-I and HDL would inhibit this process, we studied the effects of atherogenic diets on transgenic mice expressing high amounts of human ApoA-I. We report that transgenic mice with high plasma ApoA-I and HDL levels were significantly protected from the development of fatty streak lesions.