Beneficial Effects Of Fenofibrate Research Articles

Beneficial Effect of Fenofibrate in Combination with Silymarin on Parameters of Hereditary Hypertriglyceridemia-Induced Disorders in an Animal Model of Metabolic Syndrome.

Background: Hypertriglyceridemia has serious health risks such as cardiovascular disease, type 2 diabetes mellitus, nephropathy, and others. Fenofibrate is an effective hypolipidemic drug, but its benefits for ameliorating disorders associated with hypertriglyceridemia failed to be proven in clinical trials. Methods: To search for possible causes of this situation and possibilities of their favorable influence, we tested the effect of FF monotherapy and the combination of fenofibrate with silymarin on metabolic disorders in a unique model of hereditary hypertriglyceridemic rats (HHTg). Results: Fenofibrate treatment (100 mg/kg BW/day for four weeks) significantly decreased serum levels of triglyceride, (-77%) and free fatty acids (-29%), the hepatic accumulation of triglycerides, and the expression of genes encoding transcription factors involved in lipid metabolism (Srebf2, Nr1h4. Rxrα, and Slco1a1). In contrast, the hypertriglyceridemia-induced ectopic storage of lipids in muscles, the heart, and kidneys reduced glucose utilization in muscles and was not affected. In addition, fenofibrate reduced the activity of the antioxidant system, including Nrf2 expression (-35%) and increased lipoperoxidation in the liver and, to a lesser extent, in the kidneys and heart. Adding silymarin (micronized form, 600 mg/kg BW/day) to fenofibrate therapy increased the synthesis of glycogen in muscles, (+36%) and reduced hyperinsulinemia (-34%). In the liver, it increased the activity of the antioxidant system, including PON-1 activity and Nrf2 expression, and reduced the formation of lipoperoxides. The beneficial effect of combination therapy on the parameters of oxidative stress and lipoperoxidation was also observed, to a lesser extent, in the heart and kidneys. Conclusions: Our results suggest the potential beneficial use of the combination of FF with SLM in the treatment of hypertriglyceridemia-induced metabolic disorders.

Fenofibrate reduces cardiac remodeling by mitochondrial dynamics preservation in a renovascular model of cardiac hypertrophy

Fenofibrate, a PPAR-α agonist clinically used to lower serum lipid levels, reduces cardiac remodeling and improves cardiac function. However, its mechanism of action is not completely elucidated. In this study we examined the effect of fenofibrate on mitochondria in a rat model of renovascular hypertension, focusing on mediators controlling mitochondrial dynamics and autophagy.Rats with two-kidney one-clip (2K1C) hypertension were treated with fenofibrate 150 mg/kg/day (2K1C-FFB) or vehicle (2K1C-VEH) for 8 weeks. Systolic blood pressure and cardiac functional were in-vivo assessed, while cardiomyocyte size and protein expression of mediators of cardiac hypertrophy and mitochondrial dynamics were ex-vivo examined by histological and Western blot analyses.Fenofibrate treatment counteracted the development of hypertension and the increase of left ventricular mass, relative wall thickness and cross-sectional area of cardiomyocytes. Furthermore, fenofibrate re-balanced the expression Mfn2, Drp1 and Parkin, regulators of fusion, fission, mitophagy respectively. Regarding autophagy, the LC3-II/LC3-I ratio was increased in 2K1C-VEH and 2K1C-FFB, whereas the autophagy was increased only in 2K1C-FFB.In cultured H9C2 cardiomyoblasts, fenofibrate reversed the Ang II-induced mRNA up-regulation of hypertrophy markers Nppa and Myh7, accumulation of reactive oxygen species and depolarization of the mitochondrial membrane exerting protection mediated by up-regulation of the Uncoupling protein 2.Our results indicate that fenofibrate acts directly on cardiomyocytes and counteracts the pressure overload-induced cardiac maladaptive remodeling. This study reveals a so far hidden mechanism involving mitochondrial dynamics in the beneficial effects of fenofibrate, support its repurposing for the treatment of cardiac hypertrophy and provide new potential targets for its pharmacological function.

41-OR: ADA President's Select Abstract: The Beneficial Effect of Fenofibrate on Diabetic Retinopathy Is Influenced by PPARA Genetic Variability and Is Mediated by an Increase in FGF21 Levels

A PPARA genetic variant (rs6008845) influences the cardiovascular effectiveness of the PPAR-alpha agonist fenofibrate independent of changes in lipid profile. Here we investigated whether the same variant influences fenofibrate effectiveness on diabetic retinopathy (DR) . This was evaluated with regard to DR progression in 592 subjects with prior DR history from the ACCORD Eye Study, and with regard to other pre-specified diabetic eye outcomes in the ACCORD Lipid Study (n=3,650) . The effect of fenofibrate on 93 inflammatory biomarkers was studied in 320 rs6008845 T/T homozygotes from ACCORD Lipid and a large retina-eQTL dataset (GtExEye) was used to evaluate the association between rs6008845 and PPARA expression and derive a Genetic Score (eQtGS) of PPARA expression in the retina. rs6008845 modulated fenofibrate effectiveness on DR progression in a way similar to that previously reported for MACE, with the largest benefit being in rs6008845 T/T (OR 0.10, 95% C.I. 0.02-0.74) and the smallest (OR 0.54, 95% C.I. 0.21-1.42) in C/C homozygotes (p for interaction = 0.01) . The same synergism was found for severe vision loss (p=0.03) . The T allele was associated with higher PPARA retinal expression (P=4×10-38) in GtExEye, and ACCORD subjects with higher eQtGS for PPARA expression had better response to fenofibrate on DR progression (P=0.008) . Among T/T homozygotes, fenofibrate caused a marked increase in serum FGF21 (+0.87 S.D.; 95% C.I. 0.67-1.07, P=10×10-13) . Each S.D. increase in log2 FGF21 was associated with a 45% lower risk of severe vision loss (HR 0.55; 95%C.I. 0.34-0.91, p=0.01) , explaining 90% of fenofibrate benefit on this outcome in T/T subjects (p=0.03) . In conclusion, fenofibrate effectiveness on DR depends on genetic variants affecting PPARA expression and is mediated by an increase in serum FGF21 - a metabolic and anti-inflammatory cytokine that may therefore be a therapeutic target to treat diabetic eye disease. Disclosure M.Morieri: Advisory Panel; Merck Sharp & Dohme Corp., Consultant; neopharmed gentili, SLAPharma, Other Relationship; Lilly, Novo Nordisk, Servier Laboratories. H.Shah: None. Y.Tang: None. C.Mendonca: None. J.Jobe: None. J.Mychaleckyj: None. A.Doria: Research Support; Novo Nordisk Foundation. Funding NHLBI HL110400 e HL153559-Italian Ministry of Health - Ricerca Finalizzata - GR-2019-12369702.

Fenofibrat w leczeniu zaburzeń lipidowych — przegląd najnowszych doniesień

Fenofibrate has been used for many years in the treatment of lipid disorders. Its efficacy and safety have been assessed in many studies, and the evidence base continues to expand with each passing year. To supplement the knowledge on the potential of the drug in the registration indications, this paper summarizes the latest reports. As in previously published studies, also in the current reports, the beneficial effect of fenofibrate on lipid values in patients with hypertriglyceridemia or mixed dyslipidaemia (including diabetic patients) is beyond doubt confirmed. Recent studies also increasingly raise the issue of the effect of fenofibrate on hard endpoints, important both from the patient’s and physician’s perspective. The identified scientific evidence supports the thesis that in patients with type 2 diabetes or metabolic syndrome, fenofibrate therapy reduces mortality and the risk of cardiovascular events. In addition, long-term maintenance of favourable therapeutic effects, even after treatment discontinuation, was observed, as well as signals indicating potential renoprotective activity of the drug. The latest reports also confirm previous observations, according to which fenofibrate therapy is generally well-tolerated and safe. Taking the above into account, it is reasonable for this drug to maintain its place in the modern treatment of lipid disorders.

Beneficial effects of fenofibrate in pulmonary hypertension in rats.

Pulmonary hypertension(PH) is a morbid complication of cardiopulmonary as well as several systemic diseases in humans. It is rapidly progressive and fatal if left untreated. In the present study, we investigated the effect of PPARα agonist fenofibrate (FF) on monocrotaline (MCT)-induced PH in rats. FF, because of its pleiotropic property, could be helpful in reducing inflammation, oxidative stress, and reactive oxygen species. On day 1, MCT (50mg/kg, s.c.) was given to all the rats in MCT, sildenafil, and FF group except normal control rats. After 3 days of giving MCT, sildenafil (175µg/kg, orally) and FF (120mg/kg, orally) were given for 25 days. Echocardiography, hemodynamic parameters, fulton's index, histopathology, oxidative stress parameters, inflammatory markers, Bcl2/Baxgene expression ratio in the right ventricle, and protein expressionfor NOX-1 in lungs were studied in all the groups. FF has shown to prevent decrease in ratio of pulmonary artery acceleration time to ejection time, increase in ratio of right ventricular outflow tract dimension to aortic outflow dimension, rise in right ventricular systolic pressure, right ventricular hypertrophy, increase in the percentage medial wall thickness (%MWT), increase in oxidative stress and inflammation, increase in NADPH oxidase-1 (NOX-1) expression, and decrease in mRNA expression of Bcl2/Bax ratio caused by MCT. To conclude, FF prevented MCT-induced PH in rats by various mechanisms. It might be helpful in preventing PH in patients who are likely to develop PH.

Fenofibrate reverses changes induced by high-fat diet on metabolism in mice muscle and visceral adipocytes.

The effect of fenofibrate on the metabolism of skeletal muscle and visceral white adipose tissue of diet-induced obese (DIO) mice was investigated. C57BL/6J male mice were fed either a control or high-fat diet for 8 weeks. Fenofibrate (50 mg/Kg BW, daily) was administered by oral gavage during the last two weeks of the experimental period. Insulin-stimulated glucose metabolism in soleus muscles, glucose tolerance test, insulin tolerance test, indirect calorimetry, lipolysis of visceral white adipose tissue, expression of miR-103-3p in adipose tissue, and miR-1a, miR-133a/b, miR-206, let7b-5p, miR-23b-3p, miR-29-3p, miR-143-3p in soleus muscle, genes related to glucose and fatty acid metabolism in adipose tissue and soleus muscle, and proteins (phospho-AMPKα2, Pgc1α, Cpt1b), intramuscular lipid staining, and activities of fatty acid oxidation enzymes in skeletal muscle were investigated. In DIO mice, fenofibrate prevented weight gain induced by HFD feeding by increasing energy expenditure; improved whole body glucose homeostasis, and in skeletal muscle, increased insulin dependent glucose uptake, miR-1a levels, reduced intramuscular lipid accumulation, and phospho-AMPKα2 levels. In visceral adipose tissue of obese mice, fenofibrate decreased basal lipolysis rate and visceral adipocytes hypertrophy, and induced the expression of Glut-4, Irs1, and Cav-1 mRNA and miR-103-3p suggesting a higher insulin sensitivity of the adipocytes. The evidence is presented herein that beneficial effects of fenofibrate on body weight, glucose homeostasis, and muscle metabolism might be related to its action in adipose tissue. Moreover, fenofibrate regulates miR-1a-3p in soleus and miR-103-3p in adipose tissue, suggesting these microRNAs might contribute to fenofibrate beneficial effects on metabolism.

Fish oil and fenofibrate inhibit pancreatic islet hypertrophy, and improve glucose and lipid metabolic dysfuntions with different ways in diabetic KK mice

We examined the effects of fish oil and fenofibrate (FF) on the pancreatic islet hypertrophy, and on the modification of glucose and lipid metabolic dysfunctions in KK mice with insulin resistance. The mice were fed one of four diets [25en% lard/safflower oil (LSO), 25en% fish oil (FO), or each of these diets plus 0.1wt% FF (LSO/FF, FO/FF)] for 9 weeks. FO group and both FF groups had significantly lower final body and adipose tissue weights than LSO group. Pancreatic islet hypertrophy was observed only in LSO group but not in the other groups with fish oil or FF. And, it is likely that fish oil has a stronger therapeutic effect on islet hypertrophy. Plasma adiponectin level was significantly higher in FO group but not in both FF groups. Expression of hepatic lipogenic enzyme genes such as fatty acid synthase (FAS) and stearoyl-CoA desaturase-1 (SCD-1) was lower in FO groups with or without FF, whereas fatty acid oxidation-related mRNAs such as acyl-CoA oxidase (AOX) and uncoupling protein-2 (UCP-2) were more abundant in FF groups with or without fish oil. Our results suggest that both fish oil and FF improve pancreatic islet hypertrophy with the amelioration of insulin resistance. Fish oil enhances insulin sensitivity by increasing plasma adiponectin; however, the beneficial effect of FF on insulin resistance seems to be independent of the plasma adiponectin level. These results mean that improvement of glucose and lipid metabolic dysfuctions in diabetic KK mice are independently approached by fish oil and FF.

Fenofibrate pre-treatment suppressed inflammation by activating phosphoinositide 3 kinase/protein kinase B (PI3K/Akt) signaling in renal ischemia-reperfusion injury.

The aim of this study was to investigate the possible beneficial effects of Fenofibrate on renal ischemia-reperfusion injury (IRI) in mice and its potential mechanism. IRI was induced by bilateral renal ischemia for 60 min followed by reperfusion for 24 h. Eighteen male C57BL/6 mice were randomly divided into three groups: sham-operated group (sham), IRI+saline group (IRI group), IRI+Fenofibrate (FEN) group. Normal saline or Fenofibrate (3 mg/kg) was intravenously injected 60 min before renal ischemia in IRI group and FEN group, respectively. Blood samples and renal tissues were collected at the end of reperfusion. The renal function, histopathologic changes, and the expression levels of pro-inflammatory cytokines [interleukin-8 (IL-8), tumor necrosis factor alpha (TNF-α) and IL-6] in serum and renal tissue homogenate were assessed. Moreover, the effects of Fenofibrate on activating phosphoinositide 3 kinase/protein kinase B (PI3K/Akt) signaling and peroxisome proliferator-activated receptor-α (PPAR-α) were also measured in renal IRI. The results showed that plasma levels of blood urea nitrogen and creatinine, histopathologic scores and the expression levels of TNF-α, IL-8 and IL-6 were significantly lower in FEN group than in IRI group. Moreover, Fenofibrate pretreatment could further induce PI3K/Akt signal pathway and PPAR-α activation following renal IRI. These findings indicated PPAR-α activation by Fenofibrate exerts protective effects on renal IRI in mice by suppressing inflammation via PI3K/Akt activation. Thus, Fenofibrate could be a novel therapeutic alternative in renal IRI.

Fenofibrate and renal disease: clinical effects in diabetes

Fenofibrate is known to increase serum creatinine, but this effect is fully reversible, even after long-term treatment. The mechanism underlying this is poorly understood, but fenofibrate is not thought to impair true glomerular function, as measured by inulin clearance, the gold standard measure of renal function. This iatrogenic creatinine rise does not increase the risk of adverse renal outcomes or cardiovascular events. In two large randomized controlled trials of patients with Type 2 diabetes, fenofibrate was shown to be able to reduce albuminuria and slow the rate of calculated glomerular filtration rate (GFR) loss. This beneficial effect of fenofibrate on estimated GFR is only unmasked when the artificial reduction in calculated GFR is removed on drug cessation. Interestingly, in one of the trials, patients with the greatest fenofibrate-associated creatinine rise appeared to derive the greatest cardiovascular benefit.

Fenofibrate

Fenofibrate is a fibric acid derivative with lipid-modifying effects that are mediated by the activation of peroxisome proliferator-activated receptor-α. Fenofibrate also has a number of nonlipid, pleiotropic effects (e.g. reducing levels of fibrinogen, C-reactive protein, and various pro-inflammatory markers, and improving flow-mediated dilatation) that may contribute to its clinical efficacy, particularly in terms of improving microvascular outcomes. The beneficial effects of fenofibrate on the lipid profile have been shown in a number of randomized controlled trials. In primary dyslipidemia, fenofibrate monotherapy consistently decreased triglyceride (TG) levels to a significantly greater extent than placebo; significantly greater increases in high-density lipoprotein cholesterol (HDL-C) levels and significantly greater reductions in low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) levels were also seen in some trials. Monotherapy with fenofibrate or gemfibrozil had generally similar effects on TG and HDL-C levels, although in one trial, TC and LDL-C levels were reduced to a significantly greater extent with fenofibrate than with gemfibrozil. Fenofibrate monotherapy tended to improve TG and HDL-C levels to a significantly greater extent than statin monotherapy in primary dyslipidemia, whereas statin monotherapy decreased LDL-C and TC levels to a significantly greater extent than fenofibrate monotherapy. Fenofibrate also had a beneficial effect on atherogenic dyslipidemia in patients with the metabolic syndrome or type 2 diabetes mellitus, reducing TG levels, tending to increase HDL-C levels, and promoting a shift to larger low-density lipoprotein particles. In terms of cardiovascular outcomes, fenofibrate did not reduce the risk of coronary heart disease (CHD) events to a greater extent than placebo in patients with type 2 diabetes in the FIELD trial. However, the risk of some nonfatal macrovascular events (e.g. nonfatal myocardial infarction, revascularization) and certain microvascular outcomes (e.g. amputation, first laser therapy for diabetic retinopathy, progression of albuminuria) was reduced to a significantly greater extent with fenofibrate than with placebo. Subgroup analysis revealed a significant reduction in the cardiovascular disease (CVD) event rate among fenofibrate recipients in the subgroup of patients with marked hypertriglyceridemia or marked dyslipidemia at baseline. In the ACCORD Lipid trial, there were no significant differences between patients with type 2 diabetes and a high risk of CVD events who received fenofibrate plus simvastatin and those who received placebo plus simvastatin for any of the primary or secondary cardiovascular outcomes. However, fenofibrate plus simvastatin was of benefit in patients who had markedly high TG levels and markedly low HDL-C levels at baseline. In addition, fenofibrate plus simvastatin slowed the progression of diabetic retinopathy. Fenofibrate is generally well tolerated. Common adverse events included increases in transaminase levels that were usually transient, minor, and asymptomatic, and gastrointestinal signs and symptoms. In conclusion, monotherapy with fenofibrate remains a useful option in patients with dyslipidemia, particularly in atherogenic dyslipidemia characterized by high TG and low HDL-C levels.

Fenofibric acid prevents retinal pigment epithelium disruption induced by interleukin-1β by suppressing AMP-activated protein kinase (AMPK) activation

The mechanisms involved in the beneficial effects of fenofibrate on the development and progression of diabetic macular oedema (DMO) remain to be elucidated. To shed light on this issue we have explored the effect of fenofibric acid on the barrier function of human retinal pigment epithelium (RPE) cells. ARPE-19 cells (a human RPE line) were cultured for 18 days under standard conditions and under conditions leading to the disruption of the monolayer (D-glucose, 25 mmol/l, with IL-1β, 10 ng/ml, added at days 16 and 17). Fenofibric acid, 25 μmol/l and 100 μmol/l, was added on the last 3 days of the experiment (one application/day). RPE cell permeability was evaluated by measuring apical-basolateral movements of FITC-dextran (40 kDa). The production of tight junction proteins and AMP-activated protein kinase (AMPK) phosphorylation was assessed by western blot. Immunohistochemical studies of tight junction proteins and small interfering RNA transfection to AMPK were also performed in ARPE-19 monolayers. Treatment of ARPE-19 cells with fenofibric acid significantly reduced the increment of permeability and the breakdown of the ARPE-19 cell monolayer induced by D-glucose, 25 mmol/l, and IL-1β, 10 ng/ml, in a dose-dependent manner. This effect was unrelated to changes in the content of tight junction proteins. Fenofibric acid prevented the activation of AMPK induced by IL-1β and the hyperpermeability induced by IL-1β was blocked by silencing AMPK. Disruption of RPE induced by IL-1β is prevented by fenofibric acid through its ability to suppress AMPK activation. This mechanism could be involved in the beneficial effects of fenofibrate on DMO development.

Modulation of LPS-mediated Inflammation by Fenofibrate via the TRIF-dependent TLR4 Signaling Pathway in Vascular Smooth Muscle Cells

Lipopolysaccharide (LPS) induced-vascular inflammation plays a central role in vasculitis and atherosclerosis. The stimulation of toll-like receptor 4 (TLR4) by LPS elicits the release of major proinflammatory cytokines that aggravates cardiovascular disorders. Peroxisome proliferator- activated receptor Α (PPARΑ) agonists have been shown to reduce cardiovascular events by controlling lipid metabolism as well as inflammation. However, the role of PPARΑ agonist fenofibrate in modulating LPS-mediated inflammatory responses in vascular smooth muscle cells (VSMCs) remains elusive. The present study demonstrated that fenofibrate exerted a potent anti-inflammatory action through reducing interleckin-1(IL-18), tissue inhibitor of metalloproteinase-1(TIMP-1), TLR4 and enhancing PPARΑ in LPS-stimulated VSMCs. Additionally, treatment of VSMCs with the TLR4 inhibition or TLR4 small-interfering RNA illustrated that the modulatory effects of fenofibrate on LPS-mediated inflammatory responses in VSMCs were reliant on TLR4. Especially, the results suggested that beneficial effects of fenofibrate on LPS-stimulated inflammatory responses in VSMCs were mediated through interference of TLR4 and its downstream signaling components such as Toll-interleckin-1(IL-1) receptor domain- containing adaptor inducing interferon-Β (TRIF), interferon regulatory factor 3 (IRF3) and interferon-gamma inducible protein 10 (IP-10). In conclusion, PPARΑ agonist fenofibrate exerts anti-inflammatory property by antagonizing LPS-mediated inflammatory responses in VSMCs. More importantly, the modulation of the TRIF-dependent signaling pathway (TLR4/TRIF/IRF3/IP-10) might be a useful and novel anti-inflammatory strategy of fenofibrate.

Antithrombotic and antiplatelet activities of fenofibrate, a lipid-lowering drug

Fenofibrate, a lipid-lowering drug, inhibits hydroxyl-methylglutaryl coenzyme A (HMG-CoA)-reductase activity, thus reducing cholesterol synthesis and increasing the clearance of circulating LDL-cholesterol via the high affinity receptor system. In addition, fenofibrate has beneficial effects such as the inhibition of tissue factor expression, antithrombotic effect and anti-inflammatory effect. The aim of this study was to investigate the effects of fenofibrate on thrombus formation in vivo and platelet activation in vitro and ex vivo. The carotid arteries of male Sprague–Dawley rats were subjected to chemical injury by FeCl 3, and then blood flow was measured with a blood flowmeter. Fenofibrate (200 and 400 mg/kg/day for 1 week) delayed the time to occlusion by 61.3% ( p < 0.05, n = 10) and 90.7% ( p < 0.01, n = 10), respectively. Fenofibrate also significantly inhibited ex vivo platelet aggregations induced by collagen (7.5 μg/ml) ( p < 0.01, n = 11) and ADP (10 μM) ( p < 0.01, n = 11), respectively, but did not affect coagulation times following activated partial thromboplastin and prothrombin activation, indicating the antithrombotic effect was mediated by its inhibition on platelet activation rather than coagulation system. This antiplatelet activity was revealed to be mediated by the suppression of thromboxane A 2 receptor, cytosolic calcium mobilization, and cyclooxygenase (COX)-1 activity. Taken together, we demonstrate that fenofibrate can significantly inhibit artery thrombus formation in vivo, which may be due to antiplatelet activity via the inhibition of thromboxane A 2 receptor, cytosolic calcium mobilization and COX-1 activity, and the beneficial effect of fenofibrate on cardiovascular system may be also due to its modulation of platelet activation.

Beneficial effects of fenofibrate on plaque thrombogenicity and plaque stability in atherosclerotic rabbits

Fibrates are peroxisome proliferator-activated receptor alpha (PPARalpha) agonists which modulate many aspects of lipoprotein metabolism and inflammation. They have been recently demonstrated to inhibit in vitro expression of tissue factor (TF), the main initiator of blood coagulation, which probably plays a pivotal role in thrombotic complications after plaque rupture. We investigated whether a 4-week fenofibrate treatment might affect the TF expression and cellular modifications in angioplasty-induced rabbit plaque rupture. After plaque rupture by balloon angioplasty in atheromatous rabbits, animals were randomized in an untreated group or a group receiving fenofibrate. The TF content of arterial wall and the histological modifications were analyzed after 4 weeks. Fenofibrate decreased in vivo TF expression (-42%, P<.05) and plaque cholesterol content (P<.01) in iliac arteries. Fenofibrate significantly improved the reendothelialization process by 51% (P<.05) and modified cellular distribution in the plaque toward increased stabilization. These data indicate that the PPARalpha-activator fenofibrate reduces plaque thrombogenicity and accelerates endothelial regrowth which, altogether, might improve plaque stability. These effects may underlie the preventive effects of fibrate therapy in atherosclerosis complications.

Effect of fenofibrate on the level of asymmetric dimethylarginine in individuals with hypertriglyceridemia

To test whether treatment with fenofibrate decreases asymmetric dimethylarginine (ADMA) level in hypertriglyceridemic individuals. In the present study, 45 subjects with hypertriglyceridemia were recruited to receive treatment with fenofibrate (200 mg/d). Serum concentrations of ADMA, malondialdehyde (MDA), nitric oxide (NO) and tumor necrosis factor-alpha (TNF-alpha) were measured. Endothelial function assessed by flow-mediated dilation (FMD) of the brachial artery was performed. Compared with control, serum levels of ADMA (0.47+/-0.05 micromol/L in control and 0.62+/-0.28 micromol/L in hypertriglyceridemic patients, P<0.01), MDA and TNF-alpha were markedly elevated, and the level of NO was significantly reduced, concomitantly with impaired endothelium-dependent vasodilation in individuals with hypertriglyceridemia. 8-week treatment with fenofibrate significantly reduced the elevated levels of ADMA (0.53+/-0.12 micromol/L, P<0.01), MDA and TNF-alpha, attenuated the decreased level of NO and improved endothelial function. These results suggest that the beneficial effect of fenofibrate on the endothelium in hypertriglyceridemic individuals may be related to reduction of ADMA level.

Additive Beneficial Effects of Fenofibrate Combined With Atorvastatin in the Treatment of Combined Hyperlipidemia

Additive Beneficial Effects of Fenofibrate Combined With Atorvastatin in the Treatment of Combined Hyperlipidemia

Fenofibrate decreases asymmetric dimethylarginine level in cultured endothelial cells by inhibiting NF-κB activity

Previous investigations have demonstrated that endogenous inhibitors of nitric oxide synthase (NOS), such as asymmetric dimethylarginine (ADMA), contribute importantly to endothelial dysfunction, and that fenofibrate has a protective effect on the endothelium in rats treated with low-density lipoprotein (LDL) by reducing ADMA levels. In the present study, we explored further the possible mechanism underlying inhibition of ADMA generation by fenofibrate in cultured human umbilical vein endothelial cells (HUVECs). Endothelial injury was induced in cultured HUVECs by incubation with oxidative LDL (ox-LDL) and the levels of ADMA, lactate dehydrogenase (LDH), NO and tumour necrosis factor-alpha (TNF-alpha) in the conditioned medium were measured. Cell viability and the activity of dimethylarginine dimethylaminohydrolase (DDAH) and nuclear factor-kappaB (NF-kappaB) in the cultured HUVECs were also determined. Incubation of HUVECs with ox-LDL (100 microg/ml) for 24 h markedly elevated ADMA, LDH and TNF-alpha in the conditioned medium and significantly increased the activity of NF-kappaB, concomitantly with a significant decrease in the activity of DDAH and the content of NO. Pretreatment with fenofibrate (3, 10 or 30 microM) significantly inhibited the increases in ADMA, LDH and TNF-alpha, attenuated the decreased levels of NO and the decreased activity of DDAH and prevented the activation of NF-kappaB. Similar effects were observed in the presence of pyrrolidine dithiocarbamate (PDTC, 10 microM), an antagonist of NF-kappaB. The beneficial effects of fenofibrate on cultured endothelial cells were abolished by MK-886, a specific peroxisome proliferator-activated receptor-alpha (PPARalpha) antagonist. The present results suggest that fenofibrate inhibits ox-LDL-induced endothelial cell damage by decreasing ADMA and increasing DDAH activity, and the protective effects of fenofibrate on endothelial cells may be related to reduction of NF-kappaB activity by activation of the PPARalpha receptor.

Fenofibrate inhibits angiogenesis in vitro and in vivo.

Fenofibrate, a peroxisome proliferator-activated receptor (PPAR)-alpha activator, used as a normolipidemic agent, is thought to offer additional beneficial effects in atherosclerosis. Since angiogenesis is involved in plaque progression, hemorrhage, and instability, the main causes of ischemic events, this study was designed to evaluate the action of fenofibrate on angiogenesis. Our results show that fenofibrate (i) inhibits endothelial cell proliferation induced by angiogenic factors, followed at high concentrations by an increase in apoptosis, (ii) inhibits endothelial cell migration in a healing wound model, (iii) inhibits capillary tube formation in vitro, and (iv) inhibits angiogenesis in vivo. Concerning the mechanism of action, the inhibition of endothelial cell migration by fenofibrate can be explained by a disorganization of the actin cytoskeleton. At the molecular level, fenofibrate markedly decreased basic fibroblast growth factor-induced Akt activation and cyclooxygenase 2 gene expression. This inhibition of angiogenesis could participate in the beneficial effect of fenofibrate in atherosclerosis.

Activation of the peroxisome proliferator-activated receptor α protects against myocardial ischaemic injury and improves endothelial vasodilatation

BackgroundThe peroxisome proliferator-activated receptor α (PPARα) plays an important role in the metabolism of lipoproteins and fatty acids, and seems to protect against the development of atherosclerosis. To evaluate the possible protective role of PPARα on cardiovascular function, the effect of the PPARα agonist, fenofibrate was assessed with respect to ischaemia/reperfusion injury and endothelial function in mice.ResultsFenofibrate treatment reduces myocardial infarction size and improves post-ischaemic contractile dysfunction. Hearts from PPARα null mice exhibit increased susceptibility to ischaemic damages and were refractory to protection by fenofibrate treatment suggesting that the beneficial effects of fenofibrate were mediated via PPARα. Furthermore, fenofibrate improves endothelium- and nitric oxide-mediated vasodilatation in aorta and mesenteric vascular bed. A decreased inhibitory effect of reactive oxygen species in the vessel wall accounts for enhanced endothelial vasodilatation. However, the latter cannot be explained by an increase in nitric oxide synthase expression nor by an increase sensitivity of the arteries to nitric oxide.ConclusionsAltogether the present data suggest that fenofibrate exerts cardioprotective effect against ischaemia and improves nitric oxide-mediated response probably by enhancing antioxidant capacity of the vessel wall. These data underscore new therapeutic perspectives for PPARα agonists in ischaemic myocardial injury and in cardiovascular diseases associated with endothelial dysfunction.

Progression and regression of minor coronary arterial narrowings by quantitative angiography after fenofibrate therapy

To study the effects of fenofibrate, a lipid-lowering medication, on patients with coronary artery disease, 191 minor coronary narrowings in 42 patients with coronary artery disease were analyzed by quantitative coronary angiography using computer-assisted contour detection. Computed parameters were percent diameter reduction and percent plaque area. A prospectively formed intervention group of 21 patients treated with special diet and fenofibrate (200 to 400 mg/day) was checked every 6 weeks with regard to risk factors. After a mean interval of 21 months, coronary angiography was repeated, using the same x-ray system and nearly identical projections. The intervention group was angiographically compared at follow-up with an untreated comparison group, also comprising 21 patients. Both groups had high initial serum cholesterol (mean 311 mg/dl) and low-density lipoprotein (LDL) cholesterol levels (mean 235 mg/ dl). Only among the treated patients did lipid levels change significantly: cholesterol, −19%; LDL cholesterol, −20%; high-density lipoprotein cholesterol, +19%; and triglycerides, −30%. At angiographic follow-up, the changes in percent diameter reduction and percent plaque area correlated positively with the mean serum and LDL cholesterol levels of the intervention group. Significant differences were found in the change in percent plaque area between both groups. The intervention subgroup with angiographic regressions (11 patients) had significantly lower serum and LDL cholesterol levels than the intervention subgroup with angiographic progressions (10 patients). These results indicate the beneficial effect of fenofibrate on minor coronary narrowings. Because of its high reproducibility in measuring minor narrowings, quantitative coronary angiography proved to be a suitable method for angiographic follow-up.