Atherogenesis in transgenic mice expressing human apolipoprotein(a)

Lawn, Richard M.; Wade, David P.; Hammer, Robert E.; Chiesa, Giulia; Verstuyft, Judy G.; Rubin, Edward M.

doi:10.1038/360670a0

Cited by 266 publications

(153 citation statements)

References 29 publications

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“…Although the pathophysiology of atherosclerosis is quite complicated, it is unquestionable that abnormality of lipid metabolism such as a high cholesterol level causes lipid deposition in the vascular wall. Especially, apolipoproteins such as apo E and apo (a) have an important role in the development of atherosclerosis (Lawn et al 1992, Plump et al 1992, Zhang et al 1992. It is well known that the plasma apo (a) level, which is determined by genotype, is an independent risk factor for myocardial infarction (Wade et al.…”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein E-deficient mice created by systemic administration of antisense oligodeoxynucleotides: a new model for lipoprotein metabolism studies

Morishita

Gibbons²,

Kaneda³

et al. 2002

Journal of Endocrinology

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Atherosclerotic cardiovascular disease results from complex interactions among multiple genetic and environmental factors. Thus, it is important to elucidate the influence of each factor on cholesterol metabolism. For this purpose, transgenic/gene-targeting technology is a powerful tool for studying gene functions. However, this technology has several disadvantages such as being time consuming and expensive. Accordingly, we established new animal models using in vivo gene transfer technology. In this study, we examined the feasibility of the creation of a new animal model for the study of atherosclerosis. We hypothesized that apolipoprotein (apo) E-deficient mice can be created by systemic administration of antisense apo E oligodeoxynucleotides (ODN) coupled to the HVJliposome complex. Initially, we examined the localization and cellular fate of FITC-labeled antisense ODN administered intravenously. FITC-labeled ODN transfection by the HVJ-liposome method resulted in fluorescence in the liver, spleen and kidney, but not in other organs such as brain. Moreover, fluorescence with the HVJ-liposome method was sustained for up to 2 weeks after transfection, which resulted in a striking difference from transfection of ODN alone or ODN in liposomes without HVJ, which showed rapid disappearance of fluorescence (within 1 day). Given these unique characteristics of the HVJ-liposome method, we next examined transfection of antisense apo E ODN by intravenous administration. Transfection of antisense apo E ODN resulted in a marked reduction of apo E mRNA levels in the liver, but no change in apo B and -actin mRNA levels. In mice fed a normal diet, a transient increase in cholesterol and triglyceride levels was observed in the antisense apo E-treated group, but they returned to normal levels by 6 days after transfection. Similar findings were also found in mice fed a high cholesterol diet. Neither scrambled nor mismatched ODN resulted in any increase in cholesterol. To make chronic hypercholesterolemic mice, we therefore performed repeated injections of apo E antisense ODN. Whenever antisense apo E ODN were injected, mice showed a transient increase in cholesterol and triglyceride. Cumulative administration of antisense apo E ODN resulted in a sustained increase in cholesterol for up to 3 weeks after the last transfection. Finally, mice treated with repeated injections of antisense apo E every week developed sustained hypercholesterolemia and hypertriglyceridemia until withdrawal of injections. Apolipoprotein-deficient mice created by intravenous administration of antisense ODN are a promising new animal model to help understand the role of apolipoprotein in vivo and develop a new drug therapy targeting apolipoprotein.

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Section: Discussionmentioning

confidence: 99%

Apolipoprotein E-deficient mice created by systemic administration of antisense oligodeoxynucleotides: a new model for lipoprotein metabolism studies

Morishita

Gibbons²,

Kaneda³

et al. 2002

Journal of Endocrinology

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“…Indeed, Lp(a) and fibrin have been identified in atherosclerotic plaques (4-6); moreover, in transgenic mice expressing human apo(a), apo(a) co-localizes with lipid deposition on the arterial wall (7). In order to understand the basis of this connection we will briefly review the plasminogen activation system and consider recent evidence indicating that Lp(a) is a major risk factor for coronary heart disease.…”

Section: The Lipoprotein(a) Connection In Atherosclerosis and Thrombosismentioning

confidence: 99%

Structural basis for the pathophysiology of lipoprotein(a) in the athero-thrombotic process

Anglès-Cano

1997

Braz J Med Biol Res

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Lipoprotein Lp(a) is a major and independent genetic risk factor for atherosclerosis and cardiovascular disease. The essential difference between Lp(a) and low density lipoproteins (LDL) is apolipoprotein apo(a), a glycoprotein structurally similar to plasminogen, the precursor of plasmin, the fibrinolytic enzyme. This structural homology endows Lp(a) with the capacity to bind to fibrin and to membrane proteins of endothelial cells and monocytes, and thereby to inhibit plasminogen binding and plasmin generation. The inhibition of plasmin generation and the accumulation of Lp(a) on the surface of fibrin and cell membranes favor fibrin and cholesterol deposition at sites of vascular injury. Moreover, insufficient activation of TGF-ß due to low plasmin activity may result in migration and proliferation of smooth muscle cells into the vascular intima. These mechanisms may constitute the basis of the athero-thrombogenic mode of action of Lp(a). It is currently accepted that this effect of Lp(a) is linked to its concentration in plasma. An inverse relationship between Lp(a) concentration and apo(a) isoform size, which is under genetic control, has been documented. Recently, it has been shown that inhibition of plasminogen binding to fibrin by apo(a) is also inversely associated with isoform size. Specific point mutations may also affect the lysine-binding function of apo(a). These results support the existence of functional heterogeneity in apolipoprotein(a) isoforms and suggest that the predictive value of Lp(a) as a risk factor for vascular occlusive disease would depend on the relative concentration of the isoform with the highest affinity for fibrin. Correspondence

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“…These mice developed atherosclerosis due to focal apo(a) accumulation in the vessel wall leading to inhibition of transforming growth factor-␤ (TGF-␤) activity, activation of smooth muscle cells, and subsequent accumulation of lipids in the vessel wall. 11,13,14 Additionally, the atherogenic potential of Lp(a) was demonstrated in double transgenic mice expressing both human apo(a) and human apoB-100. 12 Due to its great atherogenicity, many attempts were made in the past to medicate individuals with increased Lp(a) levels with drugs or diets.…”

Section: Introductionmentioning

confidence: 99%

“…11,12 Atherogenic potential of free apo(a) was demonstrated in transgenic mice expressing human apo(a). These mice developed atherosclerosis due to focal apo(a) accumulation in the vessel wall leading to inhibition of transforming growth factor-␤ (TGF-␤) activity, activation of smooth muscle cells, and subsequent accumulation of lipids in the vessel wall.…”

Section: Introductionmentioning

confidence: 99%

Adenovirus-mediated apo(a)-antisense-RNA expression efficiently inhibits apo(a) synthesis in vitro and in vivo

et al. 2001

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Apo(a) is a very atherogenic plasma protein without apparent function, which is highly expressed in humans. The variation in plasma Lp(a) concentration among individuals is considerable. Approximately 10-15% of the white population exhibit plasma Lp(a) concentrations above the atherogenic cut-off value of approximately 30 mg/dl. Since there is currently no safe way of treating those patients with drugs, we have tested the possibility of interfering with apo(a) biosynthesis by adenovirus-mediated expression of antisense apo(a) mRNA comprising the 5Ј UTR, the signal sequence and the first three kringles of native apo(a). Transduction of rat hepatoma McA RH 7777 cells which stably expressed apo(a) with 18 kringle IV (KIV) domains with apo(a)-antisense adenovirus (AS-Ad) at multiplicity of infection (MOI) of 30 reduced

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Atherogenesis in transgenic mice expressing human apolipoprotein(a)

Cited by 266 publications

References 29 publications

Apolipoprotein E-deficient mice created by systemic administration of antisense oligodeoxynucleotides: a new model for lipoprotein metabolism studies

Apolipoprotein E-deficient mice created by systemic administration of antisense oligodeoxynucleotides: a new model for lipoprotein metabolism studies

Structural basis for the pathophysiology of lipoprotein(a) in the athero-thrombotic process

Adenovirus-mediated apo(a)-antisense-RNA expression efficiently inhibits apo(a) synthesis in vitro and in vivo

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