PPARα activator fenofibrate inhibits myocardial inflammation and fibrosis in angiotensin II-infused rats (original) (raw)
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Journal of the American College of Cardiology, 2004
We sought to clarify that a peroxisome proliferator-activated receptor-alpha (PPAR-alpha) activator inhibits myocardial fibrosis and its resultant diastolic dysfunction in hypertensive heart disease, as well as to investigate whether inflammatory mediators through the nuclear factor (NF)-kappa-B pathway are involved in the effects. BACKGROUND Patients with hypertensive heart disease often have diastolic heart failure without systolic dysfunction. Meanwhile, it has been well established in atherosclerosis that PPAR-alpha activation negatively regulates early inflammation. In hypertensive hearts, however, it is still unclear whether PPAR-alpha activation inhibits inflammation and fibrosis. METHODS Twenty-one rats were randomly separated into the following three groups: deoxycorticosterone acetate (DOCA)-salt hypertensive rats treated with a PPAR-alpha activator, fenofibrate (80 mg/kg/day for 5 weeks); DOCA-salt rats treated with vehicle only; and uninephrectomized rats as normotensive controls. RESULTS Fenofibrate significantly inhibited the elevation of left ventricular end-diastolic pressure and the reduction of the magnitude of the negative maximum rate of left ventricular pressure rise and decline, corrected by left ventricular pressure (ϪdP/dt max /P), which are indicators of diastolic dysfunction. Next, fenofibrate prevented myocardial fibrosis and reduced the hydroxyproline content and procollagen I and III messenger ribonucleic acid expression. Finally, inflammatory gene expression associated with NF-kappa-B (interleukin-6, cyclooxygenase-2, vascular cell adhesion molecule-1, and monocyte chemoattractant protein-1), which is upregulated in DOCA-salt rats, was significantly suppressed by fenofibrate. Activation of NF-kappa-B and expression of I-kappa-B-alpha in DOCA-salt rats were normalized by fenofibrate. CONCLUSIONS A PPAR-alpha activator reduced myocardial fibrosis and prevented the development of diastolic dysfunction in DOCA-salt rats. The effects of a PPAR-alpha activator may be mediated partly by prevention of inflammatory mediators through the NF-kappa-B pathway. These results suggest that treatment with PPAR-alpha activators will improve diastolic dysfunction in hypertensive heart disease.
Objective—To demonstrate, quantify, and mechanistically dissect antiatherosclerotic effects of fenofibrate besides lowering plasma cholesterol per se. Methods and Results—ApoE*3Leiden transgenic mice received either a high-cholesterol diet (HC) or HC containing fenofibrate (HCFF) resulting in 52% plasma cholesterol-lowering. In a separate low-cholesterol diet (LC) control group, plasma cholesterol was adjusted to the level achieved in the HCFF group. Low plasma cholesterol alone (assessed in LC) resulted in reduced atherosclerosis (lesion area, number and severity) and moderately decreased plasma serum amyloid-A (SAA) concentrations. Compared with LC, fenofibrate additively reduced lesion area, number and severity, and the total aortic plaque load. This additional effect in HCFF was paralleled by an extra reduction of aortic inflammation (macrophage content; monocyte adhesion; intercellular adhesion molecule-1 [ICAM-1], soluble vascular cell adhesion molecule-1, granulocyte-macrophage colony-stimulating factor (GM-CSF), MCP-1, and NF-B expression), systemic inflammation (plasma SAA and fibrinogen levels), and by an upregulation of plasma apoE levels. Also, enhanced expression of ABC-A1 and SR-B1 in aortic macrophages may contribute to the antiatherosclerotic effect of fenofibrate by promoting cholesterol efflux. Conclusion—Fenofibrate reduces atherosclerosis more than can be explained by lowering total plasma cholesterol per se. Impaired recruitment of monocytes/macrophages, reduced vascular and systemic inflammation, and stimulation of cholesterol efflux may all contribute to these beneficial effect of fenofibrate. (Arterioscler Thromb Vasc Biol. 2006;26: 2322-2330.) Key Word: atherosclerosis fibrates inflammation reverse cholesterol transport pleiotrop
2003
Objective-To demonstrate, quantify, and mechanistically dissect antiatherosclerotic effects of fenofibrate besides lowering plasma cholesterol per se. Methods and Results-ApoE*3Leiden transgenic mice received either a high-cholesterol diet (HC) or HC containing fenofibrate (HCϩFF) resulting in 52% plasma cholesterol-lowering. In a separate low-cholesterol diet (LC) control group, plasma cholesterol was adjusted to the level achieved in the HCϩFF group. Low plasma cholesterol alone (assessed in LC) resulted in reduced atherosclerosis (lesion area, number and severity) and moderately decreased plasma serum amyloid-A (SAA) concentrations. Compared with LC, fenofibrate additively reduced lesion area, number and severity, and the total aortic plaque load. This additional effect in HCϩFF was paralleled by an extra reduction of aortic inflammation (macrophage content; monocyte adhesion; intercellular adhesion molecule-1 [ICAM-1], soluble vascular cell adhesion molecule-1, granulocyte-macrophage colony-stimulating factor (GM-CSF), MCP-1, and NF-B expression), systemic inflammation (plasma SAA and fibrinogen levels), and by an upregulation of plasma apoE levels. Also, enhanced expression of ABC-A1 and SR-B1 in aortic macrophages may contribute to the antiatherosclerotic effect of fenofibrate by promoting cholesterol efflux. Conclusion-Fenofibrate reduces atherosclerosis more than can be explained by lowering total plasma cholesterol per se. Impaired recruitment of monocytes/macrophages, reduced vascular and systemic inflammation, and stimulation of cholesterol efflux may all contribute to these beneficial effect of fenofibrate. (Arterioscler Thromb Vasc Biol. 2006;26: 2322-2330.)
Life Sciences, 2013
Aims: Fenofibrate is a peroxisome proliferator-associated receptor alpha agonist (PPARα) used clinically for the management of dyslipidemia and is a myocardial fatty acid oxidation stimulator. It has also been shown to have cardiac anti-hypertrophic properties but the effects of fenofibrate on the development of eccentric LVH and ventricular function in chronic left ventricular (LV) volume overload (VO) are unknown. This study was therefore designed to explore the effects of fenofibrate treatment in a VO rat model caused by severe aortic valve regurgitation (AR) with a focus on cardiac remodeling and myocardial metabolism. Main methods: Male Wistar rats were divided in four groups (13-15 animals/group): Shams (S) treated with fenofibrate (F; 100 mg/kg/d PO) or not (C) and severe AR receiving or not fenofibrate. Treatment was started one week before surgery and the animals were sacrificed 9 weeks later. Key findings: AR rats developed severe LVH (increased LV weight) during the course of the protocol. Fenofibrate did not reduce LV weight. However, eccentric LV remodeling was strongly reduced by fenofibrate in AR animals. Fractional shortening was significantly less affected in ARF compared to ARC group. Fenofibrate also increased the myocardial enzymatic activity of enzymes associated with fatty acid oxidation while inhibiting glycolytic enzyme phosphofructokinase. Significance: Fenofibrate decreased LV eccentric remodeling associated with severe VO and helped maintain systolic function. Studies with a longer follow-up will be needed to assess the long-term effects of fenofibrate in chronic volume overload caused by aortic regurgitation.
Beneficial effects of fenofibrate in pulmonary hypertension in rats
Molecular and cellular biochemistry, 2018
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 (50 mg/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 (175 µg/kg, orally) and FF (120 mg/kg, orally) were given for 25 days. Echocardiography, hemodynamic parameters, fulton's index, histopathology, oxidative stress parameters, inflammatory markers, Bcl2/Bax gene expression ratio in the right ventricle, and protein expression for NOX-1 in lungs were studied in all the groups. FF has shown to prevent decrease in ratio of pulmonary artery acceleration time...
Molecules, 2016
Renin-angiotensin system (RAS) activation promotes oxidative stress which increases the risk of cardiac dysfunction in metabolic syndrome (MetS) and favors local insulin resistance. Fibrates regulate RAS improving MetS, type-2 diabetes and cardiovascular diseases. We studied the effect of fenofibrate treatment on the myocardic signaling pathway of Angiotensin II (Ang II)/Angiotensin II type 1 receptor (AT1) and its relationship with oxidative stress and myocardial insulin resistance in MetS rats under heart ischemia. Control and MetS rats were assigned to the following groups: (a) sham; (b) vehicle-treated myocardial infarction (MI) (MI-V); and (c) fenofibrate-treated myocardial infarction (MI-F). Treatment with fenofibrate significantly reduced triglycerides, non-high density lipoprotein cholesterol (non-HDL-C), insulin levels and insulin resistance index (HOMA-IR) in MetS animals. MetS and MI increased Ang II concentration and AT1 expression, favored myocardial oxidative stress (high levels of malondialdehyde, overexpression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4), decreased total antioxidant capacity and diminished expression of superoxide dismutase (SOD)1, SOD2 and catalase) and inhibited expression of the insulin signaling cascade: phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PkB, also known as Akt)/Glut-4/endothelial nitric oxide synthase (eNOS). In conclusion, fenofibrate treatment favors an antioxidant environment as a consequence of a reduction of the Ang II/AT1/NOX4 signaling pathway, reestablishing the cardiac insulin signaling pathway. This might optimize cardiac metabolism and improve the vasodilator function during myocardial ischemia.
Fenofibrate protects endothelial cells against the harmful effects of TNF-alpha
SA Heart
INTRODUCTION Fenofibrate, a fibric acid-derivative and peroxisome proliferatoractivated receptor-alpha (PPARα) agonist, is best known for its high density lipoprotein cholesterol increasing and triglyceride reducing effects. (1,2) In addition to its anti-dyslipidaemic actions, fenofibrate has been shown to exert several pleiotropic (nonlipid) vasculo-protective effects, including antioxidant, (3-6) antithrombotic, (7,8) and anti-apoptotic effects. (9,10) Many of the beneficial pleiotropic effects of fenofibrate on the vasculature are thought to be driven by increased endotheliumdependent nitric oxide (NO) release, as demonstrated in a study which showed that fenofibrate treatment improved hyperaemia-induced flow-mediated dilatation in patients with hypertriglyceridaemia. (1) NO is an important endotheliumderived molecule involved in the maintenance of vascular homeostasis, (11) and is synthesised by the NO synthase (NOS) enzyme family, viz. endothelial NOS (eNOS), neuronal NOS (nNOS) and inducible NOS (iNOS). (12) In addition to its NO modulatory effects, fenofibrate has been shown to possess antioxidant properties. For example, fenofibrate reduced superoxide levels and apoptosis in human umbilical vein endothelial cells (HUVECs) exposed to high glucose treatment, (10) and increased superoxide dismutase activity in rat brain microvessels. (3) Cardiovascular risk factors, such as diabetes mellitus and obesity, as well as atherosclerosis are associated with inflammation and increased levels of pro-inflammatory cytokines. (13-15) Endothelial cells are important cellular targets of pro-inflammatory cytokines such as tumour necrosis factor alpha (TNF-alpha), (16) and exposure of the endothelium to TNF-alpha can result in endothelial dysfunction. (13) In fact, TNF-alpha is considered one of the main promoters of endothelial dysfunction during the early stages of atherosclerosis. (17) Hence, investigations into potential therapeutic interventions that can prevent TNF-alpha Introduction: Fenofi brate exerts pleiotropic effects on endothelial cells (ECs) by, amongst others, increasing nitric oxide (NO) production. We aimed to investigate fenofi brate's putative benefi cial actions in healthy or TNF-alpha-induced dysfunctional ECs. Methods: Fenofi brate-induced pro-vasodilatory responses were assessed in aortic rings (50-125μM; 30min) with and without L-NMMA (100μM). Rat cardiac microvascular ECs were treated with fenofi brate (30 and 50μM; 1h). In the pre-treatment experiments, fenofi brate (50μM) was administered one hour before TNFalpha treatment (20ng/ml; 24h). NO-production (DAF-2/DA or Griess assay), mitochondrial ROS-production (MitoSox™), cell viability (propidium iodide staining), and changes in the expression/phosphorylation of critical endothelial proteins were measured by Western blotting. Results: Fenofi brate increased NO-production ˜2-fold in healthy ECs (p<0.05 vs. vehicle). A ˜2 3% pro-vasodilatory response was induced in aortic rings, which was reversed by L-NMMA (p<0.05 vs. fenofi brate). Fenofi brate pretreatment ameliorated TNF-alpha-induced endothelial dysfunction by reversing the loss of NO, improving oxidative stress, restoring cell viability and preventing caspase-3 activation. Protective effects were underpinned by ˜4 7% and ˜4 9% up-regulation of activated eNOS and AMP-kinase, respectively (p<0.05 vs. TNFalpha). Conclusions: Fenofi brate protects TNF-alpha-induced dysfunctional ECs via up-regulated eNOS-NO, reduced oxidative stress and improved cell viability. These novel fi ndings warrant further investigations to explore the potential use of fenofi brate as an anti-endothelial dysfunction therapeutic agent.
2009
Background: In view of the reported efficacy of peroxisome proliferator-activated receptor-α in renal ischemia/ reperfusion (I/R) injury, the present study was designed to investigate the effect of fenofibrate on cardiac damage induced by renal I/R in hyperlipidemic rats. Methods: Male Wistar rats were divided into five groups: Group 1, normal control; Group 2, hyperlipidemic control; Group 3, renal I/R injury; Group 4, hyperlipidemic + renal I/R injury; and Group 5, hyperlipidemic + renal I/R injury + fenofibrate. Hyperlipidemia was induced by feeding the rats with cholesterol (500 mg/kg per oral) in hydrogenated ground nut oil (as a vehicle) for 4 weeks. At the end of the fourth week, renal I/R injury was induced by occlusion of both renal vascular pedicles for 60 minutes, followed by 24-hour reperfusion. In the treatment group, fenofibrate (100 mg/kg per oral, dissolved in water containing 0.2% methyl cellulose) was given 2 weeks before I/R injury. At the end of the experiment, blood and heart were isolated for biochemical analysis. Results: Hyperlipidemic I/R rats have significantly higher levels of cardiac lipid peroxidation, xanthine oxidase, nitric oxide and myeloperoxidase, and lower levels of antioxidant enzymes (reduced glutathione, superoxide dismutase and catalase) compared to non-hyperlipidemic I/R rats, the levels of which were restored after treatment with fenofibrate. Cardiac functional enzymes were normalized after the administration of fenofibrate. Conclusion: This study elucidated the oxidative role of cardiac damage induced by renal I/R via inflammatory mediators, which was attenuated by fenofibrate.
Journal of Molecular and Cellular Cardiology, 2008
Peroxisome proliferator-activated receptors (PPARs) play an important role in the transcriptional regulation of lipid utilization and storage in several organs, including liver and heart. Our working hypothesis is that treatment of obesity/hyperlipedemia with the PPARα ligand fenofibrate leads to drainage of plasma lipids by the liver, resulting in reduced myocardial lipid supply, reduced myocardial fatty acid oxidation and improved myocardial tolerance to ischemic stress. Thus, we investigated changes in substrate utilization in heart and liver, as well as post-ischemic functional recovery in hearts from diet-induced obese (DIO) mice following long-term (11-12 weeks) treatment with fenofibrate. The present study shows that DIO mice express increased plasma lipids and glucose, as well as increased myocardial fatty acid oxidation and a concomitant decrease in glucose oxidation. The lipid-lowering effect of fenofibrate was associated with increased hepatic mitochondrial and peroxisomal fatty acid oxidation, as indicated by a more than 30% increase in hepatic palmiotyl-CoA oxidation and more than a 10-fold increase in acyl-CoA oxidase (ACO) activity. In line with an adaptation to the reduced myocardial lipid supply, isolated hearts from fenofibrate-treated DIO mice showed increased glucose oxidation and decreased fatty acid oxidation, as well as reduced ACO activity. Fenofibrate treatment also prevented the diet-induced decrease in cardiac function and improved post-ischemic functional recovery. We also found that, while fenofibrate treatment markedly increased the expression of PPARα target genes in the liver, there were no such changes in the heart. These data demonstrate that fenofibrate results in a direct activation of PPARα in the liver with increased hepatic drainage of plasma lipids, while the cardiac effect of the compound most likely is secondary to its lipid-lowering effect.