Biomedical subjects

Mohammed H Moghadasian

Publications and source records attributed to Mohammed H Moghadasian.

15 recordsLinked to original sources

PubMed2007

Fish oil significantly alters fatty acid profiles in various lipid fractions but not atherogenesis in apo E-KO mice.

BACKGROUND: Consumption of fish oil and n-3 fatty acids is associated with beneficial modifications in plasma lipid levels. The impact of these modifications on development of atherosclerotic lesions merits further investigation. AIM OF THE STUDY: The aim of this study was to investigate the impact of fish oil consumption on quality and quantity of lipoprotein fatty acids and its influence on atherosclerosis in apolipoprotein E-knockout (apo E-KO) mice. METHODS: Male apo E-KO mice were treated with 1% dietary fish oil for 14 weeks. Plasma triglycerides (TG), phospholipids, (PL) and cholesteryl ester (CE) fractions were separated using thin layer chromatography. Plasma-free fatty acids (FFA) plus fatty acid contents of TG, PL, CE were determined using gas chromatography. Aortic atherosclerosis was assessed by histological and morphometrical techniques. RESULTS: Twenty-eight fatty acids were identified in each of the four lipid compartments. High amounts of n-3 fatty acids (eicosapentaenoic (EPA), docosahexaenoic (DHA)) were found in all of these fractions. The levels of EPA and DHA increased by 400 and 150%, respectively, in FFA, TG and PL compartments; higher increases (>500 and 200%) in EPA and DHA were found in CE. This markedly decreased the n-6/n-3 ratios in FFA, TG, PL, and CE by 60, 72, 53, and 61%, respectively. These changes were accompanied by a significant increase in plasma triglyceride levels. Surprisingly, these changes did not affect atherogenesis. CONCLUSIONS: Elevated levels of EPA and DHA do not appear to prevent development of atherosclerotic plaques in this model. Longer studies warrant investigation of the direct benefits of these fatty acids against myocardial damage as clinical consequences of advanced atherosclerosis.

Animals↗

PubMed2006

Dietary phytosterols reduce cyclosporine-induced hypercholesterolemia in apolipoprotein E-knockout mice.

BACKGROUND: Cyclosporine-induced hypercholesterolemia is a major concern after solid organ transplantation. Reducing this side effect of cyclosporine by dietary agents may be safe, cost-effective, and attractive to both patients and health professionals. METHODS: In this study, the interactions between dietary phytosterols (2% w/w) and cyclosporine (0.02% w/w) in regard to blood cyclosporine concentrations, lipoprotein profile, and histological and morphometrical features of atherosclerotic lesions were studied over 14 weeks in apolipoprotein E-knockout mice. RESULTS: Cyclosporine alone increased plasma non-HDL cholesterol, and triglyceride concentrations and reduced HDL-cholesterol levels as compared to controls. However, these changes were not associated with further increases in atherogenesis as compared to controls. Unlike cyclosporine, phytosterols reduced non-HDL cholesterol and atherosclerosis, and increased HDL-cholesterol concentrations, as compared to the control group. The addition of dietary phytosterols to cyclosporine reduced the extent of cyclosporine-induced hypercholesterolemia, but not cyclosporine-induced hypertriglyceridemia. The extent of atherosclerosis in the combination therapy group was significantly lower than that in the control group or cyclosporine-treated group. Blood cyclosporine concentrations were comparable between the two groups of cyclosporine-treated and the combination therapy groups at the end of the study. CONCLUSION: This study suggests that simultaneous consumption of dietary phytosterols and cyclosporine may attenuate posttransplant hypercholesterolemia associated with the immunosuppressive cyclosporine. Additional studies are required to understand the mechanisms by which dietary phytosterols reduce cyclosporine-induced hypercholesterolemia.

Animals↗

PubMed2005

Dietary phytosterols reduce probucol-induced atherogenesis in apo E-KO mice.

We have previously shown strong pro-atherogenic effects of probucol in apolipoprotein E-knockout (apo E-KO) mice. The aims of the present study were to investigate whether (a) dietary phytosterols reduce probucol-induced atherogenesis and (b) beneficial interactions exist between these agents. Male apo E-KO mice fed with an atherogenic diet supplemented with phytosterols or probucol or their combination for 14 weeks. Single therapy with either phytosterols or probucol resulted in a 25% reduction in plasma total cholesterol (TC) concentrations as compared to the control group. The effects of the combination therapy were more profound (60% reduction). While phytosterols reduced atherogenesis by 60%, probucol caused an increase of 150% in atherogenesis. Addition of phytosterols to probucol substantially reduced pro-atherogenic effects of probucol. This was associated with improved high density lipoprotein (HDL) concentrations. The ratio of TC to HDL cholesterol was markedly reduced in the combination therapy group as compared to the probucol-treated group. A strong positive association between the ratio of TC to HDL cholesterol and the extent of atherosclerotic lesions was observed. The coronary arteries of the probucol-treated group showed various stages of atherogenesis from infiltration of monocytes into intima to complete occlusion of the vessel by atheromatous lesions. Such pathological findings were not observed in the combination therapy group. Approximately 40% of the mice in the probucol-treated group and 10% of the animals in the combination therapy group developed skin lesions. Further studies warrant the investigation of the underlying mechanisms of the observed beneficial interactions between dietary phytosterols and probucol.

Animals↗

PubMed2005

Combination of dietary phytosterols plus niacin or fenofibrate: effects on lipid profile and atherosclerosis in apo E-KO mice.

Patients with mixed dyslipidemias (increased LDL cholesterol and triglyceride as well as low HDL cholesterol levels) benefit from a combination of lipid-modifying drugs such as statins, niacin, fibrates and ezetemibe. However, safety, tolerability and cost are a concern in drug combination therapy. Dietary phytosterols reduce LDL cholesterol, and niacin or fenofibrate primarily reduces triglyceride and increases HDL-cholesterol levels. Thus, we hypothesized that a combination of phytosterols with niacin or fenofibrate will synergistically impact lipoprotein profile and atherogenesis in apo E-KO mice. Phytosterols alone significantly reduced plasma total cholesterol levels (14.1 vs. 16.9 mmol/L, P < .05) and the extent of atherosclerosis (0.42 vs. 0.15 mm(2), P < .05). The addition of fenofibrate to phytosterols increased plasma total cholesterol levels by >50% (14.1 vs. 21.6 mmol/L, P < .05) and decreased HDL-cholesterol concentrations by 50% (0.8 vs. 0.4 mmol/L). These changes were accompanied by slight reductions in the extent of atherosclerosis (0.42 vs. 0.34 mm(2), P > 0.05) as compared to controls, suggesting other potential anti-atherogenic effects of fenofibrate. Unlike fenofibrate, niacin caused an increase of 150% (P < .05) in HDL-cholesterol concentrations and a decrease of 22% (P < .05) in total cholesterol levels which were associated with significant reductions (65%, P < .05) in atherosclerotic lesion size as compared to controls. Neither the addition of niacin nor of fenofibrate reduced plasma triglyceride levels. In conclusion, the addition of niacin to phytosterols synergistically increases HDL-cholesterol levels, while a combination of phytosterols and fenofibrate results in no synergistic effects in apo E-KO mice. Further studies in other animal models are needed to establish synergetic effects between these lipid-modifying dietary and pharmacological agents.

Animals↗

PubMed2005

Antiatherogenic effects of dietary plant sterols are associated with inhibition of proinflammatory cytokine production in Apo E-KO mice.

Dietary phytosterols significantly reduce atherosclerosis in apo E-deficient mice. Because atherosclerosis is a chronic inflammatory disease, we investigated whether the antiatherogenic effects of phytosterols are associated with reductions in proinflammatory cytokine production as well as the effect of this diet on global immunocompetence. Apolipoprotein (apo) E-deficient mice were fed a cholesterol-supplemented diet in the presence or absence of 2% dietary phytosterols for 14 wk and then immunized with ovalbumin. The relations between plasma lipid concentrations, atherosclerotic lesions, and cytokine production and proinflammatory stimuli or foreign antigens were characterized. Phytosterol-enriched diets were strongly associated with reduced plasma cholesterol concentrations and atherosclerosis in conjunction with higher anti-inflammatory [interleukin (IL)-10] and lower proinflammatory cytokine [IL-6, tumor necrosis factor (TNF)-alpha] production. In contrast, development of cytokine and chemokine responses to ovalbumin was as strong as or even improved in the phytosterol-treated mice relative to controls. The antiatherogenic effects of dietary phytosterols in apo E-knockout mice were associated with beneficial alterations in both lipoprotein metabolism and inflammatory pathways. Decreased capacity to mount proinflammatory cytokine and chemokine responses to inflammatory stimuli did not interfere with the global immunocompetence of such mice. Thus, the desirable suppression of proinflammatory cytokine production that was associated with inhibition of atherogenesis did not impair the capacity to mount responses to foreign antigens.

Animal Feed↗

PubMed2005

Paradoxical effects of fenofibrate and nicotinic acid in apo E-deficient mice.

Atherosclerosis is a complex vascular disease initiated by abnormal accumulation of plasma lipoproteins in the subendothelial space. Elevated levels of plasma triglycerides (TG) and low-density lipoprotein (LDL)-cholesterol as well as low concentrations of high-density lipoprotein (HDL) play a causal role in the development and progression of atherosclerotic lesions. We have shown that apolipoprotein E-deficient (apo E-KO) mice have elevated triglyceride levels plus diminished HDL concentrations. Drugs such as fenofibrate and nicotinic acid are well known to reduce TG and increase HDL levels in humans. In this study, we investigated the beneficial effects of fenofibrate and niacin on lipid profile and atherogenesis in apo E-KO mice and their wild-type counterparts. Animals were fed with a cholesterol-enriched diet supplemented with fenofibrate (0.1% wt/wt, n = 8) or nicotinic acid (0.5% wt/wt, n = 8) for 14 weeks. Body weights were recorded weekly, and plasma lipid profiles were determined at 4-week intervals. The hearts and aortas were collected and fixed for histologic and morphometric evaluations of atherosclerotic lesions. Fenofibrate treatment in apo E-KO mice paradoxically increased total cholesterol and TG by 65% and 44%, respectively, and decreased HDL-cholesterol levels by 35% as compared with controls. Similar effects of fenofibrate on cholesterol levels, but not on TG concentrations, were observed in C57BL/6 mice. Fenofibrate-treated mice had lower body weight as compared with controls. Niacin had no effect on body weight gain but failed to decrease TG or to increase HDL levels in either apo E-KO mice or their wild-type counterparts. Neither fenofibrate nor niacin significantly influenced atherogenesis in apo E-KO mice as compared with controls. In conclusion, this study shows that neither niacin nor fenofibrate has beneficial lipid-modifying and antiatherosclerosis activities in mice. Identification of mechanisms underlying paradoxical effects of fenofibrate on lipoprotein metabolisms in apo E-KO mice merits further investigation.

Animals↗

PubMed2004

Species-related variations in lipoprotein metabolism: the impact of FER(HDL) on susceptibility to atherogenesis.

Several animal models have been used to investigate the mechanisms of atherogenesis. Each animal species has advantages and disadvantages with regard to similarity with human lipoprotein metabolism. In humans, fractional esterification rate in apolipoprotein B-depleted plasma (FER(HDL)) has been shown to correlate with the quality of high density lipoprotein particles. Increased values of FER(HDL) indicate an atherogenic lipoprotein profile. Such an association has not been defined in animal models. Thus, we have characterized plasma lipoprotein profile and FER(HDL) values in four animal species namely, cats, pigs, guinea pigs and rabbits. These animal species have been used in experimental dyslipidemia and atherosclerosis. Our data indicate a wide rage of variations among various animal species. High-density lipoprotein (HDL) particles contain approximately 40% of total plasma cholesterol concentrations in rabbits, pigs and cats <10% in guinea pigs. A negative association between FER(HDL) values and plasma HDL-cholesterol levels was observed in pigs, rabbits and guinea pigs. On the other hand, FER(HDL) values showed a positive association with plasma triglyceride levels in all animal species tested. These findings are in agreement with data reported in humans. More research is needed to identify the better animal models which closely resemble human lipoprotein metabolism.

Animals↗

PubMed2004

Cerebrotendinous xanthomatosis: clinical course, genotypes and metabolic backgrounds.

Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive metabolic disease. It has been reported in more than 200 people worldwide. This review covers the epidemiologic, biochemical and molecular characteristics of the disease, its clinical symptoms and treatment. A search of MEDLINE, using the keywords cerebrotendinous xanthomatosis, brain xanthoma, tendon xanthoma, cholestanol, cholesterol and bile alcohol for articles covering clinical manifestations, laboratory findings, pathology, molecular defects and treatment of CTX, revealed 175 patients with documented CTX. Of these patients, 56% were female. The incidence of tendon xanthomas was 71%, cataracts 92%, low intelligence 81% and other neurologic symptoms 100%. Several genetic studies have revealed mutations in the sterol 27-hydroxylase gene, resulting in markedly diminished activity of the enzyme in CTX patients. This genetic defect is associated with elevated plasma cholestanol levels and consequently its accumulation in the brain, lens, tendons and other tissues. The disease can be treated by the administration of chenodeoxycholic acid, a cost-effective therapy that will considerably reduce the socioeconomic burden of treating patients with CTX. The mechanism of cholestanol accumulation in affected tissues and its pathogenesis are undefined and therefore warrant further investigation.

Bile Acids and Salts↗

PubMed2003

Ultrastructural evidence of early endothelial damage in coronary arteries of rat cardiac allografts.

BACKGROUND: Events that occur early after transplantation, particularly immune recognition of allo-endothelium, initiate transplant vascular disease (TVD). Previous work suggests an important compromise of endothelial integrity as the allo-immune milieu evolves, although mechanisms by which integrity is altered remain unclear. Increased vascular permeability caused by endothelial damage may allow inflammatory cells, lipoproteins, other proteins, and plasma fluid to enter the sub-endothelial space, thereby contributing to the initiation of atherosclerosis. In this study, we examined endothelial integrity in coronary arteries and the proximal aorta after cardiac transplantation in rats. METHODS: We used Lewis-to-Lewis and Lewis-to-F344 rat heterotopic cardiac transplant models. We studied the effects of cyclosporine (5mg/kg/day) therapy compared with saline-treated controls. En face silver nitrate staining was performed to demonstrate endothelial cell borders and gaps. We used scanning electron microscopy to extend silver nitrate findings and to further define the presence and nature of endothelial disruptions. We used transmission electron microscopy to further characterize immune cell identity and interaction with endothelium. RESULTS: Syngrafts and cyclosporine-treated allografts showed normal-looking endothelium similar to that observed in arteries from native hearts. However, saline-treated allografts displayed progressive endothelial destruction, including large intercellular gaps, missing cells, and areas of bare extracellular matrix. Exfoliated surfaces were covered by platelets at various stages of adhesion, activation, and spreading. Similarly, we observed numerous leukocytes as either adherent to the endothelial lining or transmigrating into the sub-endothelial space. Cessation of cyclosporine therapy was associated with the development of similar abnormalities. CONCLUSIONS: Our findings indicate that, especially when immunosuppression is insufficient, early endothelial damage may promote vascular permeability and thereby initiate TVD.

Animals↗

PubMed2003

Disodium ascorbyl phytostanyl phosphate reduces plasma cholesterol concentrations and atherosclerotic lesion formation in apolipoprotein E-deficient mice.

Disodium ascorbyl phytostanyl phosphate (FM-VP4) consists of ascorbic acid covalently bound to phytostanols by a phosphodiester linkage and is derived as the disodium salt. The purpose of this study was to evaluate the lipid-lowering and antiatherosclerotic properties of FM-VP4 following administration to apolipoprotein E (ApoE)-deficient mice. Four-week-old male C57BL/6J mice with a homozygous deletion of the ApoE gene (apolipoprotein E knock-out) were administered 0 (control), 0.1%, 0.5%, 1.0%, and 2.0% (wt/vol) FM-VP4 in their drinking water or 2.0% FM-VP4 (wt/wt) in their diet for 12 consecutive weeks. All animals received a standard mouse chow diet consisting of 9.0% (wt/wt) fat and 0.2% (wt/wt) cholesterol. Plasma cholesterol and triglyceride levels were determined at baseline and at 4-week intervals (4, 8, and 12 weeks) throughout the term of the study. At the end of the study, mice were killed using CO(2) gas, and blood was taken from the heart. The heart and aorta were removed and sections of the aortic roots were stained with oil red O (ORO) and Movat's stain. The lesions found in this area were measured using a computer-assisted image analysis. Consumption of FM-VP4 by either food or drinking water routes was associated with an approximately 75% reduction in total plasma cholesterol levels and a 75% decrease in aortic atherosclerotic lesion area in ApoE-deficient mice over 12 weeks compared to controls. A trend in decreasing plasma triglyceride levels was also observed. Taken together these data suggest that FM-VP4 has both lipid-lowering and antiatherosclerotic properties following 12-week administration to ApoE-deficient mice.

Animals↗

PubMed2002

Experimental atherosclerosis: a historical overview.

Almost one-hundred years ago the first evidence of experimental atherosclerosis was reported. Over the past century, significant advances have been made in the development of animal models of human coronary artery disease. In this minireview, induction of atherosclerotic lesions in several animal models including rodents (mice, rabbits, rats, hamsters, guinea pigs), avian (pigeons, chickens, quail), swine, carnivora (dogs, cats), and non-human primates is discussed. The limitations and advantages of the animal models of atherosclerosis have been summarized. The transgenic/knockout animal models have greatly enhanced our understanding of atherosclerosis. Compared to wild-type counterparts, the knockout/transgenic animals develop atherogenesis faster without a need for a highly atherogenic diet. Although almost all investigations support a causal role for increased plasma cholesterol levels in the development of atherosclerotic vascular disease, an increasing body of evidence indicates serious invqlvement of other factors including oxidative stress, inflammation, infection and other emerging risk factors.

Animals↗

PubMed2002

Cerebrotendinous xanthomatosis: a rare disease with diverse manifestations.

This mini-review deals with a new appraisal of cerebrotendinous xanthomatosis. In addition to neurologic symptoms, patients with cerebrotendinous xanthomatosis develop cataracts, diarrhea, Achilles tendon xanthoma, atherosclerotic vascular disease, and many other abnormalities. Although the pathophysiology of the disease is not completely understood, excess production and consequent accumulation of cholestanol in tissues may play a crucial role. Chenodeoxycholic acid is the most effective therapy. The causative role and detrimental effects (at a low plasma level) of cholestanol merit further investigation.

Brain Diseases↗

PubMed2002

A safety look at currently available statins.

In this mini-review, the evidence for safety and efficacy of currently available statins is discussed. Large-scale, long-term clinical studies have documented an outstanding efficacy and safety profile for statin monotherapy when used at pharmacological doses. Non-life-threatening side effects may occur in up to 15% of patients receiving one statin. Sporadic reports show possible adverse effects of statins on nervous system function including mood alterations. More serious side effects may also occur but at much lower rates. Significant elevations in the activity of serum aminotransferase and creatine kinase alone or in combination with muscle pain in statin-treated patients should be taken seriously; under these conditions, monitoring the statin dose or its discontinuation must be considered. Unlike monotherapy, combination therapy is more problematic. Particularly, combination of the statins with gemfibrozil results in higher rates of drug toxicity. Co-administration of statins with other drugs, especially those which may interfere with the cytochrome P450 system, should be considered carefully. Special attention must be paid to the tolerability of the statins in elderly and transplant patients. The safety of statins in children and adolescents has not yet been well-documented, thus, statin therapy is not routinely recommended in this group of hyperlipidaemic subjects. Future clinical studies and surveillance information will warrant long-term safety of each member of this class of lipid-lowering agents.

Adolescent↗

PubMed2002

Statins and menopause.

During the reproductive period, women generally have lower low-density lipoprotein (LDL) cholesterol and higher high-density lipoprotein cholesterol than age- and diet-matched men. However, these possibly antiatherogenic characteristics of lipoproteins are changed to a potentially atherogenic profile after menopause. Menopause-related changes in lipoprotein profile can be corrected by the administration of hormone replacement therapy (HRT). However, the results of recent studies did not show definite benefits of HRT on coronary heart disease-related mortality rates. On the other hand, several large-scale, long-term clinical trials provide evidence for efficacy and safety of HMG-CoA reductase inhibitors (statins) in both men and women. The results of 19 short-term clinical trials using simvastatin, pravastatin, fluvastatin or lovastatin in postmenopausal women are summarised and discussed. All these investigations reported significant reductions in both total and LDL cholesterol levels. The question of whether statin therapy results in a significant decrease in cardiovascular-related mortality rates along with a better quality of life in postmenopausal women remains to be investigated in large-scale, randomised, double-blind, placebo-controlled clinical trials.

Age Factors↗

PubMedDate not supplied

Comparison of cholesterol-lowering efficacy and anti-atherogenic properties of hydrogenated versus non-hydrogenated (Phytrol) tall oil-derived phytosterols in apo E-deficient mice.

The cholesterol-lowering and anti-atherogenic effects of non-hydrogenated (FCP-3P1 containing 69% beta-sitosterol, 16% sitostanol, and 13% campesterol) and hydrogenated (FCP-3P2 containing 77% sitostanol, 11% campestanol, and 8% beta-sitosterol) Phytrol trade mark have been compared in apo E-deficient mice. After consumption of 0.2% (w/w) cholesterol-enriched diet, the elevated plasma cholesterol levels observed in controls was significantly reduced by the addition of either 0.5%, 1% or 2% FCP-3P1 or FCP-3P2 at week 4. Compared to controls, the treatment of 0.5%, 1%, and 2% FCP-3P1 in the diet resulted in reduction in cholesterol concentrations by 33.6%, 46.8% and 52.4% at week 8, respectively, whereas the reduction in plasma cholesterol levels by 0.5%, 1%, and 2% FCP-3P2 was only 20.5%, 38.7% and 31.7% indicating lower cholesterol-lowering effect of the hydrogenated phytosterols at all doses as compared with non-hydrogenated phytosterols (FCP-3P1). By contrast, FCP-3P1 and FCP-3P2 showed comparable non-significant anti-atherogenic properties in treated animals after 14-week treatment. 0.5%, 1%, and 2% FCP-3P1 treated apo E-deficient mice had a mean aortic lesion area that was smaller than controls although the reduction of atherosclerotic lesions did not reach the statistical significance. In conclusion, this study did not show statistically significant differences between hydrogenated and non-hydrogenated plant sterols with regard to their cholesterol-lowering and anti-atherosclerotic properties in apo E-KO mice.

Animals↗