Animal Model Of Hyperlipidemia Research Articles

Fluvastatin, HMG-CoA Reductase Inhibitor: Antiatherogenic Profiles Through Its Lipid-Lowering-Dependent and -Independent Actions

Fluvastatin, the first totally synthetic inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, has the unique structure of a mevalonolactone derivative of a fluorophenyl-substituted indole ring. Fluvastatin markedly reduces plasma lipid levels in animals and humans by inhibiting the activity of HMG-CoA reductase following the up-regulation of low density lipoprotein receptors, as it occurs with other HMG-CoA reductase inhibitors. Several lines of evidence indicate that the hypolipidemic action of fluvastatin results in antiatherosclerotic effects in hyperlipidemic animal models. Recent findings have shown, however, that fluvastatin inhibits the progression of atherosclerosis independent of its lipid-lowering effects. In addition, fluvastatin inhibits key events or factors in the initiation or progression of atherosclerosis. These effects include antioxidant and antithrombotic properties, improvement of endothelial function, inhibition of activated monocyte-endothelial cell interaction, and inhibition of activated macrophage and smooth muscle cell function. Recent large clinical trials with fluvastatin demonstrated its beneficial effects on the incidence of clinical events and on the progression of atherosclerotic plaques in patients with hyperlipidemia. Although angiographic changes (e.g., the decrease in minimum lumen diameter) in response to therapy were modest, the accompanying clinical benefit appeared to be significant. The lipid-lowering therapy can not fully explain the results of clinical trials. The antiatherogenic profiles of fluvastatin might contribute to the decrease in the clinical events by directly inhibiting the atherosclerotic plaque progression and stabilizing the atherosclerotic plaque lesion. Elucidation of pleiotropic effects of fluvastatin other than lipid-lowering properties encourages the clinical use of fluvastatin not only for the reduction of plasma cholesterol levels but also for the secondary prevention of coronary heart disease in patients with hypercholesterolemia.

Dietary Phytoestrogens to Prevent Cardiovascular Disease

A multitude of substances are present in small amounts in plants that can affect mammalian biological processes relevant to cardiovascular disease and other common human diseases.1 However, few of the thousands of bioactive molecules have been studied well in cells or animals, and still fewer in humans. This slim evidence base notwithstanding, a staggering array of these compounds are available for our use as pricey nutritional supplements. The phytoestrogens are arguably the most intensively studied of these substances, and as a result, conclusions about them can be drawn with good scientific support. Phytoestrogens are a subcategory of compounds called flavonoids, a group composed of hundreds or more types of molecules. The 2 classes of phytoestrogens are isoflavones, notably found in soy products, and lignans, present in nuts, fruits, cereal grains, tea, and coffee.1–3 Because of their assumed health benefit, isoflavone content is advertised in many foods that contain soybeans, and isoflavones are sold as nutritional supplements. See p 465 The phytoestrogen hypothesis stemmed from several independent lines of evidence.2–4 One was the recognition that phytoestrogens had estrogenic effects in animals. Another came from epidemiological studies in Asia showing a low prevalence of cardiovascular disease and hormone-dependent cancers of the breast, endometrium, and prostate. A third was the well-established animal model of hyperlipidemia and atherosclerosis that used casein, a milk protein, and that was reversed by soy protein, which often contained isoflavones. This combination of animal experiments and human epidemiological evidence coalesced into a strong hypothesis that natural phytoestrogens present in soybeans and other plant foods had wide-ranging …

Green tea catechins inhibit neointimal hyperplasia in a rat carotid arterial injury model by TIMP-2 overexpression.

Although it has been demonstrated that the antioxidant properties of tea catechins reduce atherosclerotic lesions in various animal models of hyperlipidemia, it is not yet clear whether these catechins prevent hyperlipidemia-independent arterial remodeling induced by balloon angioplasty. We evaluated the influence of the administration of the tea extract on vascular remodeling in a rat carotid artery balloon-injury model. Male Wistar rats were supplied drinking water with or without green tea extract (1 mg/ml) supplement. Administration of the tea extract reduced the area of the intima (30%) and the ratio of the intimal area to the medial area (36.2%) in injured arteries compared with those of control rats at 14 days after the injury. Real-time RT-PCR, Western blot, and gelatin zymography revealed a significant increase in tissue inhibitor of matrix metalloproteinase (MMP)-2 (TIMP-2) expression as well as a significant reduction of gelatinolytic net activity and activated MMP-2 levels in the injured arteries as a result of the administration of the tea extract compared with those of control group. Similarly, epigallocatechin-3-gallate, a major constituent of green tea catechins, significantly upregulated TIMP-2 expression in cultured smooth muscle cells. Immunohistochemical analysis showed that the increase of TIMP-2 protein occurred preferentially in the developing neointima. These results indicate that catechins inhibit intimal hyperplasia in a rat balloon-injury model through the upregulation of TIMP-2 expression to modulate MMP activity.

Comparison of animal models of hyperlipidemia

To select the proper experimental animal model for research on prevention and treatment of hyperlipidemia. Hyperlipidemia models of mouse, rat, golden hamster, guinea pig, rabbit, pigeon and quail often used in the last ten years were compared. Golden hamster and guinea pig models are similar to human beings in lipid metabolism and have unique superiority in experimental study, while the models of rat, mouse, pigeon and quail have significant difference as compared with human beings. Rabbit is one of the best animal models in studying new drugs for regulating lipid and treating arteriosclerosis. Factors such as the required time, indexes, the duration of making models, and the cost and feeding of animals should be considered in selecting animal models according with the experimental requirements.

DRF 2655: a unique molecule that reduces body weight and ameliorates metabolic abnormalities.

Preclinical evaluation of DRF 2655, a peroxisome proliferator-activated receptor alpha (PPARalpha) and PPARgamma agonist, as a body-weight lowering, hypolipidemic and euglycemic agent. DRF 2655 was studied in different genetic, normal, and hyperlipidemic animal models. HEK 293 cells were used to conduct the reporter-based transactivation of PPARalpha and PPARgamma. To understand the biochemical mechanism of lipid-, body-weight-, and glucose-lowering effects, activities of key beta-oxidation and lipid catabolism enzymes and gluconeogenic enzymes were studied in db/db mice treated with DRF 2655. 3T3L1 cells were used for adipogenesis study, and HepG2 cells were used to study the effect of DRF 2655 on total cholesterol and triglyceride synthesis using [(14)C]acetate and [(3)H]glycerol. DRF 2655 showed concentration-dependent transactivation of PPARalpha and PPARgamma. In the 3T3L1 cell-differentiation study, DRF 2655 and rosiglitazone showed 369% and 471% increases, respectively, in triglyceride accumulation. DRF 2655 showed body-weight lowering and euglycemic and hypolipidemic effects in various animal models. db/db mice treated with DRF 2655 showed 5- and 3.6-fold inhibition in phosphoenolpyruvate carboxykinase and glucose 6-phosphatase activity and 651% and 77% increases in the beta-oxidation enzymes carnitine palmitoyltransferase and carnitine acetyltransferase, respectively. HepG2 cells treated with DRF 2655 showed significant reduction in lipid synthesis. DRF 2655 showed excellent euglycemic and hypolipidemic activities in different animal models. An exciting finding is its body-weight lowering effect in these models, which might be mediated by the induction of target enzymes involved in hepatic lipid catabolism through PPARalpha activation.

Comparison of maritime pine oil and fish oil effects on plasma lipoproteins in apolipoprotein E-deficient mice

The goal of this study was to compare the lipid lowering properties of maritime pine and fish oils in apolipoprotein E-deficient (KOE) mice, an animal model of hyperlipidemia. KOE mice were supplemented with either lard, fish or maritime pine oil (10% w/w) for one month. Compared to lard, fish and maritime pine oils decreased cholesterol (−31% and −52% respectively) and phospholipid (−41 and −52%) levels and increased triglyceride (+182% and +123%) levels. These lipid changes resulted in an enrichment in triglycerides and a depletion in cholesterol of VLDL+IDL plasma fraction as compared to lard-fed mice. These findings suggest that VLDL-triglyceride lipolysis is impaired in KOE mice fed fish or maritime pine oil.

Alpha1-adrenergic plus angiotensin receptor blockade reduces atherosclerosis in apolipoprotein E-deficient mice.

-We have used the apolipoprotein E (apoE)-deficient mouse model to determine whether both the angiotensin II type 1 (AT1) and the alpha1-adrenergic receptors influence arteriosclerotic changes in this hyperlipidemic animal model. Mice were treated with antihypertensive drugs beginning at 9 weeks of age, and aortic atherosclerosis was measured after 12 weeks of treatment. Systolic blood pressure in the untreated apoE-deficient mouse averaged 104 mm Hg throughout the treatment period. Prazosin at a dose of 7.5 mg. kg-1. d-1 was ineffective in attenuating atherosclerosis and did not significantly reduce blood pressure. Losartan, at dosages of either 20 or 30 mg. kg-1. d-1, also did not influence atherosclerosis and had only a slight blood pressure-lowering effect. However, combined treatment with both prazosin and losartan markedly reduced atherosclerotic lesion development from an average lesion size per section of 2.6 to 1.5x10(5) microm2 (P<0.001) and significantly reduced blood pressure to 85+/-5 mm Hg. Treatment with NG-nitro-L-arginine methyl ester (40 mg. kg-1. d-1) produced significant elevations of blood pressure (127+/-3.8 mm Hg) but had no effect on the development of atherosclerosis. None of the treatments used affected plasma cholesterol throughout the 12-week period. These studies suggest that the vascular changes associated with atherosclerosis are influenced by a combination of AT1 and alpha1-adrenergic receptor activation.

The poloxamer 407-induced hyperlipidemic atherogenic animal model.

We are attempting to develop a chemically-induced murine model for the study of atherosclerosis. Injection of poloxamer-407 (P-407) into rats and mice causes significant dose-dependent hypercholesterolemia and hypertriglyglyceridemia. The elevated triglycerides (TG) seem to result primarily from the compound's inhibition of lipoprotein lipase. P-407 also indirectly stimulates the activity of the rate limiting enzyme in cholesterol (CHOL) biosynthesis, HMG CoA reductase. In addition, P-407 promotes changes in the concentration of hepatic CHOL content. These date indicate that the hyper CHOL could be the result of increased CHOL synthesis, as well as a clearing of CHOL from the liver. Chronic injection into mice of P-407 for 145 d produced atherogenic lesions in the aortas of C57BL/6 mice. The response was equivalent to that seen in animals eating a high CHOL diet for 145 d. Cholic acid potentiated the P-407-induced atherogenesis. These data suggest that P-407 could be used as an agent for the study of hyperlipidemia-induced atherogenesis.

Pharmacology of carvedilol: rationale for use in hypertension, coronary artery disease, and congestive heart failure.

Carvedilol is a novel, multiple-action cardiovascular drug that is currently approved in many countries for the treatment of hypertension. The reduction in blood pressure produced by carvedilol results primarily from beta-adrenoceptor blockade and vasodilation, the latter resulting from alpha 1-adrenoceptor blockade. These actions, as well as several of the other activities of carvedilol, are associated with cardioprotection in animal models that occurs to a degree that is greater than that observed with other drugs. The multiple actions of carvedilol may also provide the underlying rationale for the use of the drug in the treatment of coronary artery disease and congestive heart failure. By virtue of being both a beta-blocker and a vasodilator, carvedilol significantly decreases myocardial work by reducing all three components of myocardial oxygen demand, namely, heart rate, contractility, and wall tension. The vasodilatory effects of carvedilol reduce afterload, and the resulting decrease in impedance to left ventricular ejection offsets the negative inotropic effect that would normally result from beta-blockade. As a consequence, stroke volume and cardiac output are maintained or even increased in animals and in patients with congestive heart failure who are treated with carvedilol. Carvedilol and several of its metabolites are potent antioxidants, and this activity may account, in part, for the cardioprotective effects of the drug observed in animal models of acute myocardial ischemia and, in theory, could also serve to protect the myocardium of patients with hypertension, coronary artery disease, and congestive heart failure, in which oxidative stress is now recognized to occur. The antioxidant effects of carvedilol may both inhibit the direct cytotoxic actions of reactive oxygen radicals and prevent oxygen-radical induced activation of transcription factors and genes associated with inflammatory and remodeling processes. Accordingly, carvedilol inhibits the gene expression of the intracellular adhesion molecule-1 (ICAM-1), an adhesion molecule for polymorphonuclear leukocytes, which typically infiltrate the myocardium under conditions of ischemia and may exacerbate ischemic injury. The antioxidant activity of carvedilol has been shown to inhibit the oxidation of low density lipoprotein (LDL) in vitro, thereby preventing the formation of this cytotoxic and atherogenic form of LDL. It follows, therefore, that in animal models of hyperlipidemia, carvedilol attenuates aortic lipid accumulation and decreases the aortic content of monocytes and foam cells, and at the same time it has been shown to preserve endothelial integrity and function. These actions of carvedilol are not shared by other beta-blockers or by other drugs currently used in the management of hypertension, coronary artery disease, or congestive heart failure. The multiple actions of carvedilol may provide the underlying pharmacologic rationale for the use of this drug in the treatment of patients with coronary artery disease or congestive heart failure, and these actions may account, at least in part, for the reduction in mortality produced by carvedilol in clinical trials involving patients with congestive heart failure. Likewise, these actions of carvedilol may also provide protection, beyond that afforded from reduction in blood pressure, against secondary organ damage in hypertensive patients treated with the drug.

Angiotensin converting enzyme inhibition and coronary artery disease

To review the evidence on the effects of angiotensin converting enzyme (ACE) inhibitors in coronary artery disease. In studies of experimental atherosclerosis involving hypertensive and normotensive hyperlipidemic animals, ACE inhibitors have had potent anti-atherogenic effects, reducing the total aortic intimal surface involved and the aortic cholesterol content. In balloon-injured animals, ACE inhibitors have suppressed the myointimal proliferative response in rats and rabbits, but not in higher species such as pigs and baboons, indicating possible species-specific effects. In spontaneously hypertensive rats, ACE inhibitors have modulated alterations in endothelium-related vasodilation, although similar effects have not been observed in human hypertension. ACE inhibition has not been shown to prevent restenosis after percutaneous transluminal coronary angioplasty. However, cardiac ischemic events have been prevented by ACE inhibition in patients with coronary artery disease and left ventricular dysfunction in a number of studies, including the Studies of Left Ventricular Dysfunction (SOLVD), Survival and Ventricular Enlargement (SAVE) study, Acute Infarction and Ramipril Efficacy (AIRE) study and the Gruppo Italiano per lo Studio della Streptochinesi dell'Infarto Micardico 3 (GISSI-3) trial. Other ongoing studies such as the QUinapril Ischemic Event Trial (QUIET) are assessing ACE inhibitor effects in patients with coronary artery disease and a normal left ventricular function. ACE inhibitors prevent the development of atherosclerosis in hyperlipidemic animal models. They also prevent the myointimal proliferative response to injury in some animal models, but not in higher animal species or in humans. They can reduce the number of cardiac ischemic events in patients with coronary artery disease and left ventricular dysfunction; their effects in those patients with a normal left ventricular function are now being assessed.

Effects of an Angiotensin II Receptor Antagonist on the Progression of Renal Failure in Hyperlipidemic Imai Rats

This study was undertaken to determine the role of angiotensin II (AII) in the development of glomerulosclerosis, using an AII receptor antagonist in an animal model of hyperlipidemia. Hyperlipidemic Imai rats were employed because they spontaneously develop glomerulosclerosis; this is especially true in males. Group 1 (n = 5) received no specific therapy. Group 2 (n = 5) was treated with enalapril at a dosage of 50 mg/l in drinking water starting at 6 weeks of age. Group 3 (n = 5) and group 4 (n = 6) were treated with the AII receptor antagonist DuP 753 at a respective dosage of 15 mg/l (low-dose DuP) and 150 mg/l (high-dose DuP) in drinking water. Body weight, blood pressure, urinary protein, serum albumin, cholesterol, BUN and serum creatinine were measured and compared among the groups from 12 to 24 weeks of age. Enalapril and high-dose DuP were almost equally effective in controlling systemic hypertension. Each treatment significantly reduced proteinuria (172 +/- 112 and 152 +/- 72 mg/kg/day at 24 weeks) as compared with that in the controls (421 +/- 147 mg/kg/day; p < 0.05 and p < 0.01, respectively). Hypercholesterolemia also decreased (82 +/- 4 and 89 +/- 6 mg/dl) as compared with that of the controls (141 +/- 48 mg/dl; both p < 0.05). Glomerulosclerosis index (SI) was significantly higher in the untreated control rats (55 +/- 26) than in the enalapril-treated rats (2 +/- 3; p < 0.005) and the high-dose-DuP-treated rats (6 +/- 6, p < 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

Oxygen free radicals and lipid peroxidation in genetic hyperlipidemia animal models

An instrumented tableting machine yields some of the most significant information about the compressional and ejectional forces involved in the tableting operation. A number of versions of instrumented tablet presses are commercially available but tend to be very expensive to be used widely in academic institutions. The present project involving the instrumentation of a single punch tableting machine (Manesty, Model F3) was undertaken to propose a low cost alternative to researchers in the area of product development. This paper deals with the measurement of the compression force using strain gauges mounted in two different configurations: upper punch and lower pin. Good linearity between applied force and measured strain was observed.