Regression of Advanced Atherosclerosis in Swine

Daoud, A.S.; Fritz, K. E.; Augustyn, Joan M.; Jarmolych, J.

doi:10.1007/978-3-663-06754-2_23

Cited by 22 publications

(13 citation statements)

References 11 publications

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“…Swine and nonhuman primates develop advanced lesions with fibrous caps, necrotic cores, and calcification after prolonged fat feeding. Such models have shown that advanced lesions can regress, at least to some extent, following lipid lowering, 19,39 -40 and that regression is associated with a reduction in foam cells and with thicker fibrous caps, 39 whereas calcification is less susceptible to regression. 19,39 In the mouse, few models exist that allow studies on regression of advanced lesions following lipid lowering.…”

Section: Discussionmentioning

confidence: 99%

“…Such models have shown that advanced lesions can regress, at least to some extent, following lipid lowering, 19,39 -40 and that regression is associated with a reduction in foam cells and with thicker fibrous caps, 39 whereas calcification is less susceptible to regression. 19,39 In the mouse, few models exist that allow studies on regression of advanced lesions following lipid lowering. In the study by Tsukamoto et al, 41 regression of well characterized advanced lesions containing smooth muscle cells, necrotic cores, and extracellular lipid in the aortic root and arch of apoE-deficient mice was induced by hepatic overexpression of human apoE3.…”

Section: Discussionmentioning

confidence: 99%

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Aggressive Very Low-Density Lipoprotein (VLDL) and LDL Lowering by Gene Transfer of the VLDL Receptor Combined with a Low-Fat Diet Regimen Induces Regression and Reduces Macrophage Content in Advanced Atherosclerotic Lesions in LDL Receptor-Deficient Mice

MacDougall

Kramer

Polinsky

et al. 2006

The American Journal of Pathology

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Very low-density lipoprotein (VLDL) and LDL plasma levels are associated with cardiovascular mortality. Whereas VLDL/LDL lowering causes regression of early atherosclerotic lesions, less is known about the effects of aggressive lipid lowering on regression of advanced complex lesions. We therefore investigated the effect of VLDL/LDL lowering on pre-existing lesions in LDL receptor-deficient mice. Mice fed a highfat diet for 16 weeks developed advanced lesions with fibrous caps, necrotic cores, and cholesterol clefts in the brachiocephalic artery. After an additional 14 weeks on a low-fat diet, plasma cholesterol levels decreased from 21. Dyslipidemia is a central risk factor for cardiovascular disease and is the primary target for prevention of cardiovascular mortality.1 Modification of low-density lipoproteins (LDL) is considered a key contributor to cardiovascular disease in the general population.2 Furthermore, levels of VLDL/triglycerides are often elevated in patients with type 2 diabetes or the metabolic syndrome, 3 and increased level of triglycerides is considered a risk factor for atherosclerotic heart disease in patients with and without diabetes. 4,5 The great majority of acute clinical cardiovascular events, myocardial infarction and stroke, are believed to be caused by unstable atherosclerotic lesions.6,7 Studies of human atherosclerotic lesions have indicated that most clinically relevant lesions are composed of necrotic cores covered by thin fibrous caps containing macrophage-rich re-

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Aggressive Very Low-Density Lipoprotein (VLDL) and LDL Lowering by Gene Transfer of the VLDL Receptor Combined with a Low-Fat Diet Regimen Induces Regression and Reduces Macrophage Content in Advanced Atherosclerotic Lesions in LDL Receptor-Deficient Mice

MacDougall

Kramer

Polinsky

et al. 2006

The American Journal of Pathology

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“…Regression occurred despite the absence of macrophage-derived apoE, indicating that macrophage-derived apoE is not required for induction of atherosclerotic lesion regression. Although regression of atherosclerosis has been demonstrated in other animal models, [1][2][3][4][5][6] those studies mostly involved dietary manipulations over several months to years, and the degree of quantitative regression was generally modest. In contrast, regression induced by hepatic expression of apoE3 in apoE-deficient mice was rapid and the extent of regression was marked.…”

Section: Discussionmentioning

confidence: 99%

“…egression of atherosclerosis has been demonstrated in several animal models, [1][2][3][4][5][6] largely through dietary manipulation of cholesterol levels. Regression is characterized by morphological changes in lesions, such as increased fibrotic components and decreased lipid and inflammatory components.…”

mentioning

confidence: 99%

Rapid Regression of Atherosclerosis Induced by Liver-Directed Gene Transfer of ApoE in ApoE-Deficient Mice

Tsukamoto

Tangirala

Chun

et al. 1999

ATVB

100

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Abstract-Apolipoprotein E (apoE) is a multifunctional protein synthesized by the liver and tissue macrophages.ApoE-deficient mice have severe hyperlipidemia and develop accelerated atherosclerosis on a chow diet. Both liver-derived and macrophage-derived apoEs have been shown to reduce plasma lipoprotein levels and slow the progression of atherosclerosis in apoE-deficient mice, but regression of atherosclerosis has not been demonstrated in this model. We utilized second-generation adenoviruses to achieve hepatic expression of human apoE in chow-fed, apoE-deficient mice with established atherosclerotic lesions of different stages. As expected, hepatic expression of human apoE3 significantly reduced plasma cholesterol levels. Liver-derived apoE also accumulated substantially within preexisting atherosclerotic lesions, indicating that plasma apoE gained access to the arterial intima. Hepatic expression of human apoE3 for 6 weeks resulted in significant quantitative regression of both early fatty streak lesions as well as advanced, complex lesions in both the aortic root and the aortic arch. In addition, hepatic expression of apoE induced substantial morphological changes in lesions, including decreased foam cells and increased smooth muscle cells and extracellular matrix content. In parallel, human apoE4 and apoE2 were also expressed in the liver by using recombinant adenoviruses. ApoE4 reduced cholesterol levels to the same extent as did apoE3 and also prevented progression but did not induce significant regression of preexisting lesions. ApoE2 reduced cholesterol levels to a lesser degree than did apoE3 and apoE4 and lesion progression was reduced, but regression was not induced. In summary, (1) regression of preexisting atherosclerotic lesions in apoE-deficient mice can be rapidly induced by hepatic expression of apoE, despite the absence of macrophage-derived apoE; (2) the morphological changes seen in this model of regression resemble those in other animal models, induced over longer periods of time; (3) liver-derived apoE gained access to and was retained by intimal atherosclerotic lesions; and (4) apoE4 was less effective in inducing regression, despite its effects on plasma lipoproteins that were similar to those of apoE3. The rapid regression of preexisiting atherosclerotic lesions induced by apoE gene transfer in apoE-deficient mice could provide a convenient murine model for investigation of the molecular events associated with atherosclerosis regression.

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“…Pure regression of experimental atherosclerotic lesions has been shown in chick [99], dog [100], swine [101] and non-human primates [102], leaving no doubt that relatively advanced lesions can reduce in size over time. Although human lesions may be more mature when treatment gets started, rendering the lesions more fatty, cellular and fibrous, regression of lesions has been shown in several studies [103][104][105].…”

Section: Fish Oil and The Regression Of A Th Erosclerosismentioning

confidence: 99%

Fish oil and the prevention and regression of atherosclerosis

Sassen

Lamers

Verdouw

1994

Cardiovasc Drug Ther

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Summary. Epidemiological studies in the seventies have put forward that dietary rather than genetic factors are responsible for the lower incidence of ischemic heart disease in Greenland Inuit and have generated a large body of both in vitro and in vivo experimental studies, exploring the putative favorable effects of fish (oil) on atherogenesis and its risk factors. The first part of this report reviews the in vivo animal studies, concentrating on the hypercholesterolemic models and the arterialized vein graft model. In the hypercholesterolemic animal studies, the results are inconclusive as the studies reporting a protective effect are matched by the number of studies showing no effect or an adverse effect. The diversity in species, dose of fish oil, duration of study, type of vessel studied and type of fish oil preparation (content of n-3 fatty acids, unesterified n-3 fatty acids, ethylesters or triglyceridcs) could all contribute. Furthermore, the definitions and criteria used in the literature to evaluate atherogenesis are diverse and it appears that while one parameter is affected, another is not necessarily modified in the same direction, stressing the importance of extending the analysis of the effects on atherogenesis to more than one parameter. We also believe that it is time to reach a consensus as to which animal model mimicks most closely a particular human situation. Only in appropriate models, investigating more than one atherosclerosis variable, can the effects of a putative anti-atherogenic drug or diet be verified. In the veno-arterial autograft model, mimicking the patient after coronary bypass grafting, dietary fish oil has been consistently effective in preventing accelerated graft intima proliferation. It could therefore be of interest to evaluate the effects of fish oil on graft patency in patients after coronary bypass surgery after a period of years.The results from studies on restenosis after percutaneous transluminal angioplasty are also reviewed and it is concluded that the two large scale trials, that are currently underway, might reliably answer the question whether fish oil is effective as a non-pharmacological adjuvants in the prevention of restenosis.Lastly, the studies on the effects of fish oil on the regression of experimental atherosclerosis are reviewed. In view of the small number of studies (i.e., four) investigating the effects of fish oil on the regression of atherosclerosis, it is premature to draw any conclusion, and therefore further experimental work is required.

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Regression of Advanced Atherosclerosis in Swine

Cited by 22 publications

References 11 publications

Aggressive Very Low-Density Lipoprotein (VLDL) and LDL Lowering by Gene Transfer of the VLDL Receptor Combined with a Low-Fat Diet Regimen Induces Regression and Reduces Macrophage Content in Advanced Atherosclerotic Lesions in LDL Receptor-Deficient Mice

Aggressive Very Low-Density Lipoprotein (VLDL) and LDL Lowering by Gene Transfer of the VLDL Receptor Combined with a Low-Fat Diet Regimen Induces Regression and Reduces Macrophage Content in Advanced Atherosclerotic Lesions in LDL Receptor-Deficient Mice

Rapid Regression of Atherosclerosis Induced by Liver-Directed Gene Transfer of ApoE in ApoE-Deficient Mice

Fish oil and the prevention and regression of atherosclerosis

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