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*  Telmisartan Improves Insulin Resistance of Skeletal Muscle Through Peroxisome Proliferator-Activated Receptor-δ Activation |...
The mechanisms of the improvement of glucose homeostasis through angiotensin receptor blockers are not fully elucidated in hypertensive patients. We investigated the effects of telmisartan on insulin signaling and glucose uptake in cultured myotubes and skeletal muscle from wild-type and muscle-specific peroxisome proliferator-activated receptor (PPAR) δ knockout (MCK-PPARδ−/−) mice. Telmisartan increased PPARδ expression and activated PPARδ transcriptional activity in cultured C2C12 myotubes. In palmitate-induced insulin-resistant C2C12 myotubes, telmisartan enhanced insulin-stimulated Akt and Akt substrate of 160 kDa (AS160) phosphorylation as well as Glut4 translocation to the plasma membrane. These effects were inhibited by antagonizing PPARδ or phosphatidylinositol-3 kinase, but not by PPARγ and PPARα inhibition. Palmitate reducing the insulin-stimulated glucose uptake in C2C12 myotubes ...
  http://diabetes.diabetesjournals.org/content/62/3/762.short
*  Telmisartan Improves Insulin Resistance of Skeletal Muscle Through Peroxisome Proliferator-Activated Receptor-δ Activation |...
The mechanisms of the improvement of glucose homeostasis through angiotensin receptor blockers are not fully elucidated in hypertensive patients. We investigated the effects of telmisartan on insulin signaling and glucose uptake in cultured myotubes and skeletal muscle from wild-type and muscle-specific peroxisome proliferator-activated receptor (PPAR) δ knockout (MCK-PPARδ−/−) mice. Telmisartan increased PPARδ expression and activated PPARδ transcriptional activity in cultured C2C12 myotubes. In palmitate-induced insulin-resistant C2C12 myotubes, telmisartan enhanced insulin-stimulated Akt and Akt substrate of 160 kDa (AS160) phosphorylation as well as Glut4 translocation to the plasma membrane. These effects were inhibited by antagonizing PPARδ or phosphatidylinositol-3 kinase, but not by PPARγ and PPARα inhibition. Palmitate reducing the insulin-stimulated glucose uptake in C2C12 myotubes ...
  http://diabetes.diabetesjournals.org/content/62/3/762.short?patientinform-links=yes&legid=diabetes
*  Decreased hepatic peroxisome proliferator-activated receptor-γ contributes to increased sensitivity to endotoxin in obstructive...
AIM To investigate the role of hepatic peroxisome proliferator-activated receptor-γ (PPAR-γ) in increased susceptibility to endotoxin-induced toxicity in rats with bile duct ligation during endotoxemia. METHODS Male Sprague-Dawley rats were subjected to bile duct ligation (BDL). Sham-operated animals served as controls. DNA binding were determined by polymerase chain reaction, Western blotting analysis, and electrophoretic mobility shift assay, respectively. BDL and sham-operated rats received a non-lethal dose of intraperitoneal lipopolysaccharide (LPS) injection (3 mg/kg, i.p.). Additionally, the potential beneficial effects of the PPAR-γ agonist rosiglitazone were determined in BDL and sham-operated rats treated with a non-lethal dose of LPS. Survival was assessed in BDL rats treated with a non-lethal dose of LPS and in sham-operated rats treated at a lethal dose of LPS (6 mg/kg, i.p.). RESULTS PPAR-γ activity in rats undergoing BDL was significantly ...
  https://www.semanticscholar.org/paper/Decreased-hepatic-peroxisome-proliferator-activate-Lv-Song/14514336f819cd142dfee0f3f53b8612309d3cb5
*  Peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) ligands do not potentiate growth of human cancer cell lines :...
Ligands for peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) increase skeletal muscle fatty acid catabolism, improve insulin sensitivity, increase serum high-density lipoprotein cholesterol, elicit anti-inflammatory activity and induce terminal differentiation. Contradictory findings are also reported suggesting that PPARβ/δ ligands potentiate tumorigenesis by increasing cell proliferation, by inhibiting apoptosis through phosphorylation of Akt and by increasing cyclooxygenase-2 (COX2) and vascular endothelial growth factor (VEGF) expression. The contradictory findings could be due to differences in the model system (cancer cell line versus in vivo), differences in cell culture conditions (with and without serum) or differences in ligands. The present study examined the effect of two different PPARβ/δ ligands (GW0742 and GW501516) in human cancer cell lines (HT29, HCT116, LS-174T, HepG2 and HuH7) cultured in the ...
  http://oxfordindex.oup.com/view/10.1093/carcin/bgm183
*  Role of the peroxisome proliferator-activated receptor-γ (PPAR-γ) and its natural ligand 15-deoxy-Δ12,14-prostaglandin J2 in...
The peroxisome proliferator-activated receptor-γ (PPAR-γ) is a member of a large group of nuclear receptors controlling the proliferation of peroxisomes that is involved in the downregulation of macrophage functions. Here, we report that PPAR-γ was constitutively expressed in rat primary microglial cultures and that such expression was downregulated during microglial activation by endotoxin (LPS). The presence of the PPAR-γ natural ligand 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) counteracted the repression of PPAR-γ expression caused by LPS. In microglial cultures stimulated by LPS, interferon-γ (IFN-γ) or by their combination, 15d-PGJ2 reduced the production of nitric oxide (NO) and the expression of inducible NO synthase (iNOS). The inhibitory effect was dose-dependent and did not involve an elevation of cyclic AMP, a second messenger known to inhibit NOS expression in microglia. In addition, 15d-PGJ2 down-regulated other microglial ...
  http://onlinelibrary.wiley.com/doi/10.1046/j.1460-9568.2000.00110.x/full
*  Metabolites | Free Full-Text | Metabolomic and Lipidomic Analysis of the Heart of Peroxisome Proliferator-Activated Receptor-γ...
The peroxisome proliferator-activated receptor-γ coactivators (PGC-1) are transcriptional coactivators with an important role in mitochondrial biogenesis and regulation of genes involved in the electron transport chain and oxidative phosphorylation in oxidative tissues including cardiac tissue. These coactivators are thought to play a key role in the development of obesity, type 2 diabetes and the metabolic syndrome. In this study we have used a combined metabolomic and lipidomic analysis of cardiac tissue from the PGC-1β null mouse to examine the effects of a high fat diet on this organ. Multivariate statistics readily separated tissue from PGC-1β null mice from their wild type controls either in gender specific models or in combined datasets. This was associated with an increase in creatine and a decrease in taurine in the null mouse, and an increase in myristic acid and a reduction in long chain polyunsaturated fatty acids for both genders. The most profound changes were ...
  http://www.mdpi.com/2218-1989/2/2/366/notes
*  Interference With Peroxisome Proliferator-Activated Receptor-γ in Vascular Smooth Muscle Causes Baroreflex Impairment and...
S-P467L mice expressing dominant negative peroxisome proliferator-activated receptor-γ selectively in vascular smooth muscle exhibit impaired vasodilation, augmented vasoconstriction, hypertension, and tachycardia. We hypothesized that tachycardia in S-P467L mice is a result of baroreflex dysfunction. S-P467L mice displayed increased sympathetic traffic to the heart and decreased baroreflex gain and effectiveness. Carotid arteries exhibited inward remodeling but no changes in distensibility or stress/strain. Aortic depressor nerve activity in response to increased arterial pressure was blunted in S-P467L mice. However, the arterial pressure and heart rate responses to aortic depressor nerve stimulation were unaltered in S-P467L mice, suggesting that the central and efferent limbs of the baroreflex arc remain intact. There was no transgene expression in nodose ganglion and no change in expression of the acid-sensing ion channel-2 or -3 in nodose ganglion. There was a trend toward decreased ...
  http://hyper.ahajournals.org/content/early/2014/06/09/HYPERTENSIONAHA.114.03553
*  Peroxisome Proliferator-Activated Receptor-δ Upregulates 14-3-3ε in Human Endothelial Cells via CCAAT/Enhancer Binding Protein...
Here, we investigated the mechanisms by which PPARδ agonists control expression of 14-3-3ε, a key antiinflammatory protein in endothelial cells.12 Our data not only provide evidence that PPARδ modulates expression of YWHAE gene and 14-3-3ε protein under resting conditions but also demonstrate that this nuclear receptor upregulates 14-3-3ε expression by targeting transcription via a PPRE-independent pathway involving colocalization of C/EBPβ and PPARδ on YWHAE promoter. Several lines of evidence support these conclusions. First, PPARδ agonists regulated YWHAE promoter activity in a concentration- and time-dependent manner. Concordantly, YWHAE promoter was upregulated by PPARδ overexpression, whereas specific PPARγ and PPARα ligands had no effect on YWHAE promoter under our experimental conditions. Second, PPARδ activation increased 14-3-3ε ...
  http://circres.ahajournals.org/content/100/5/e59
*  Regulation of Peroxisome Proliferator-Activated Receptor-γ by Angiotensin II Via Transforming Growth Factor-β1-Activated p38...
In the present study, we examined PPARγ regulation by Ang II in mouse aortic VSMCs. The findings of this study demonstrate that Ang II decreases expression of PPARγ via AT1 receptors in VSMCs. Furthermore, this Ang II-induced decrease in PPARγ occurs via TGF-β1 and the p38 MAPK pathway. Ang II activated p38 via TGF-β1 and decreased PPARγ through HDAC3 without involving Smad signaling.. In this study, blockade of AT1 receptors with losartan inhibited Ang II-induced PPARγ reduction. AT1 receptors mediate most responses to Ang II, and this receptor subtype is predominantly expressed in VSMCs.25,26 AT1 receptor antagonists have been shown to activate PPARγ in various cell types, including adipocytes and VSMCs.27,28 Among the various AT1 receptor antagonists, telmisartan has been shown to activate PPARγ within a 10 μmol/L concentration,28 whereas the losartan activates PPARγ only ...
  http://atvb.ahajournals.org/content/32/2/397.long
*  Peroxisome proliferator-activated receptor gamma - Wikipedia
Peroxisome proliferator-activated receptor gamma (PPAR-γ or PPARG), also known as the glitazone receptor, or NR1C3 (nuclear receptor subfamily 1, group C, member 3) is a type II nuclear receptor that in humans is encoded by the PPARG gene. PPARG is mainly present in adipose tissue, colon and macrophages. Two isoforms of PPARG are detected in the human and in the mouse: PPAR-γ1 (found in nearly all tissues except muscle) and PPAR-γ2 (mostly found in adipose tissue and the intestine). PPARG regulates fatty acid storage and glucose metabolism. The genes activated by PPARG stimulate lipid uptake and adipogenesis by fat cells. PPARG knockout mice fail to generate adipose tissue when fed a high-fat diet. This gene encodes a member of the peroxisome proliferator-activated receptor ...
  https://en.wikipedia.org/wiki/Peroxisome_proliferator-activated_receptor_gamma
*  Pulmonary Arterial Hypertension Is Linked to Insulin Resistance and Reversed by Peroxisome Proliferator-Activated Receptor-γ...
Although a link between insulin resistance and systemic cardiovascular disease is evident in both clinical2 and experimental studies,3,33 this report is the first indication that there may be a possible link with PAH. If insulin resistance does contribute to the pathobiology of PAH in humans, it will be an extremely important relationship owing to the steadily increasing number of children, adolescents,1 and adults2 with the metabolic syndrome, which includes insulin resistance as a key element.. ApoE−/− mice of both genders on HF showed atheroma on histology and on micro-CT, affecting the large PAs in a nonocclusive manner. Similar features have been described in pathological specimens of adult patients with PAH.38 However, the cholesterol levels and the presence of atheroma were similar in male and female apoE−/− mice, but only male apoE−/− developed insulin resistance and severe PAH (ie, a combination of marked RVSP elevation, RVH, and enhanced peripheral PA muscularization). We ...
  http://circ.ahajournals.org/content/115/10/1275
*  Increased Expression of Peroxisome Proliferator-Activated Receptor-α and -γ in Blood Vessels of Spontaneously Hypertensive Rats...
The present study demonstrates that both PPAR-α and PPAR-γ are expressed in various rat tissues, including blood vessels, heart, muscle, kidney, liver, and adipose tissue. There is a differential expression of PPAR-α and PPAR-γ during development in SHR, a genetic model of hypertension, compared with control WKY rats. We demonstrate for the first time that in aorta from young, prehypertensive SHR, PPAR-α and PPAR-γ levels are similar, whereas in mesenteric arteries from young SHR, PPAR-α and PPAR-γ levels were greater than in age-matched WKY. In established hypertension in adult SHR, however, PPAR-α and PPAR-γ levels in aorta and mesenteric arteries were greater than in age-matched WKY. Cell culture confirmed the expression of PPARs, particularly PPAR-γ, in VSMCs.. Expression of PPARs was ...
  http://hyper.ahajournals.org/content/38/2/249
*  Cardiomyocyte-Specific Knockout and Agonist of Peroxisome Proliferator-Activated Receptor-γ Both Induce Cardiac Hypertrophy in...
Cardiac hypertrophy is characterized by increased protein synthesis44 and size of existing cardiomyocytes,45 leading to increased cardiac muscle mass.46 Agonists of nuclear receptor PPAR-γ have been shown to inhibit both protein synthesis and cardiac hypertrophy induced by pressure overload.10,11 To elucidate the physiological function of PPAR-γ in cardiomyocytes, we used Cre-loxP system to genetically inactivate this gene specifically in cardiomyocytes of CM-PGKO mice.. CM-PGKO mice displayed age-progressive cardiac hypertrophy, indicating that PPAR-γ normally suppresses cardiomyocyte growth. Despite this hypertrophy, the resting cardiac systolic function in CM-PGKO mice was comparable to littermate control mice at the age of 6 months. In fact, at this time point, there may be a subtle improvement in systolic function over baseline, which may lead to the lower resting HR that was noted. Whether function will be maintained ...
  http://circres.ahajournals.org/content/97/4/372
*  Endothelin-1-Induced Cardiac Hypertrophy Is Inhibited by Activation of Peroxisome Proliferator-Activated Receptor-α Partly Via...
In this study, we demonstrated that activation of PPAR-α interrupted the earliest ET-1-induced events, ie, JNK activation, c-Jun phosphorylation, and c-Jun induction in cardiomyocytes. Because JNKs regulate the AP-1 DNA binding activity through phosphorylation of the 2 serine residues in the NH2-terminal region of c-Jun, 1 of the AP-1 components,19 fenofibrate, would inhibit AP-1 activity partly via JNK pathway inhibition. Activation of ERK has been implicated in features of the hypertrophic response in an in vitro model.10 Also in our study, ERKs were markedly activated by ET-1 in cardiomyocytes, but this was not affected by fenofibrate. Therefore, the inhibitory effect of fenofibrate on ET-1-related hypertrophic responses might be mediated through interfering with the JNK pathway rather than the ERK pathway.. We demonstrated that fenofibrate inhibited ET-1 promoter activity, preproET-1 mRNA expression, and hypertrophy in ET-1-stimulated cardiomyocytes. To gain additional insight into the ...
  http://circ.ahajournals.org/content/109/7/904
*  Peroxisome Proliferator-Activated Receptor-γ Activation With Angiotensin II Type 1 Receptor Blockade Is Pivotal for the...
Impairment of the BBB is a critical event in the development and progression of several diseases that affect the CNS. We demonstrated here that increased BBB permeability with downregulation of TJ and AJ proteins was involved in T2DM-induced cognitive impairment. TJs present between cerebral endothelial cells perform diffusion barrier functions of the BBB and consist of many proteins, such as claudin 3, claudin 5, occludin, and ZO-1. On the other hand, AJs are required for the correct organization of TJs and are largely composed of VE-cadherin in endothelial cells.1 Therefore, alteration of the interaction between these TJ proteins and VE-cadherin plays an essential role in modulating BBB function. Our results are consistent with these ideas and previous observations, suggesting that reduced ZO-1 and occludin expression, for example, might contribute to enhanced BBB permeability in diabetes mellitus.10 However, further alterations of BBB ultrastructure in ...
  http://hyper.ahajournals.org/content/59/5/1079
*  Microparticles in Angiogenesis | Circulation Research
Few studies have analyzed the effects of total circulating MPs, the physiological or pathophysiological real conditions, on angiogenesis. Recently, we have shown that circulating MPs from peroxisome proliferator-activated receptor-α wild-type mice, but not from knockout mice, induce the formation of capillary-like structures of endothelial cells. This effect, however, was abolished when the NF-κB pathway was inhibited, indicating the involvement of a mechanism dependent on NF-κB activation.50 Thus, peroxisome proliferator-activated receptor-α/NF-κB pathways activated by MPs may play a pivotal stimulatory role for angiogenesis of endothelial cells.. It has been shown that platelet MPs are able to modify steps involved in angiogenesis, such as proliferation, migration, and adhesion of endothelial cells. Kim et al53 were pioneers to demonstrate that platelet MPs increased proliferation, chemotatic migration, and formation of capillary-like tubes of human ...
  http://circres.ahajournals.org/content/109/1/110
*  Microparticles in Angiogenesis | Circulation Research
Few studies have analyzed the effects of total circulating MPs, the physiological or pathophysiological real conditions, on angiogenesis. Recently, we have shown that circulating MPs from peroxisome proliferator-activated receptor-α wild-type mice, but not from knockout mice, induce the formation of capillary-like structures of endothelial cells. This effect, however, was abolished when the NF-κB pathway was inhibited, indicating the involvement of a mechanism dependent on NF-κB activation.50 Thus, peroxisome proliferator-activated receptor-α/NF-κB pathways activated by MPs may play a pivotal stimulatory role for angiogenesis of endothelial cells.. It has been shown that platelet MPs are able to modify steps involved in angiogenesis, such as proliferation, migration, and adhesion of endothelial cells. Kim et al53 were pioneers to demonstrate that platelet MPs increased proliferation, chemotatic migration, and formation of capillary-like tubes of human ...
  http://circres.ahajournals.org/content/109/1/110.full
*  Peroxisome Proliferator-Activated Receptor-α and Receptor-γ Activators Prevent Cardiac Fibrosis in Mineralocorticoid-Dependent...
Thank you for your interest in spreading the word on Hypertension.. NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address. ...
  http://hyper.ahajournals.org/content/early/2003/07/14/01.HYP.0000083511.91817.B1
*  "Peroxisome Proliferator-Activated Receptor-γ Coactivator 1-α (PPARGC1A" by Amanpreet K. Cheema
Genetic heterogeneity, lifestyle factors, gene-gene or gene-environment interactions are the determinants of T2D which puts Hispanics and populations with African ancestry at higher risk of developing T2D. In this dissertation, the genetic associations of PPARGC1A polymorphisms with T2D and its related phenotypes (metabolic markers) in Haitian Americans (cases=110, controls=116), African Americans (cases=120, controls=124) and Cuban Americans (cases=160, controls=181) of South Florida were explored. Five single nucleotide polymorphisms of gene PPARGC1A were evaluated in each ethnicity for their disease association. In Haitian Americans, rs7656250 (OR= 0.22, pp=0.03) had significant protective association with T2D but had risk association in African Americans for rs7656250 (OR=1.02, p=0.96) and rs4235308 (OR=2.53, p=0.03). We found that in Haitian American females, both rs7656250 (OR=0.23, pp=0.03) had protective association with T2D. In African American females, rs7656250 ...
  http://digitalcommons.fiu.edu/etd/1577/
*  Hypercholesterolemia Induces Side-Specific Phenotypic Changes and Peroxisome Proliferator-Activated Receptor-γ Pathway...
To examine the complex and multifactorial processes in early AVS in vivo, we combined a broad genomics-based approach with precise spatial resolution in a large animal model. To our knowledge, the present study is the first to examine the valve endothelium in the earliest stages of AVS and to identify a spatial shift of phenotype balance in response to a brief systemic insult. We found that the aortic side endothelium is much more responsive to HC than the adjacent ventricular side endothelium, and unexpectedly expressed overall protective pathways on the side vulnerable to AVS.. Differential endothelial responses to HC were identified using four different genomewide comparisons: two within-animal comparisons, in which the aortic and ventricular sides were compared; and two between-animal comparisons, in which the effect of HC on a single side of the valve was considered. These single-side analyses between NC and HC swine provided insight about the within-animal comparisons. For example, the ...
  http://atvb.ahajournals.org/content/30/2/225
*  Role of Mitochondrial Dysfunction in Insulin Resistance | Circulation Research
Fewer and smaller-sized mitochondria are found in skeletal muscle of insulin-resistant, obese, or T2DM subjects.34-36 The number and size of mitochondria are correlated with mitochondrial oxidative capacity.10 The decreased mitochondrial oxidative capacity accompanies the reduction in expression of mitochondrial proteins encoded by both the mitochondrial genome (cytochrome c oxidase 1) and nucleus (succinate dehydrogenase and pyruvate dehydrogenase).34 The molecular mechanism of mitochondrial biogenesis is driven, in part, through peroxisome proliferator-activated receptor (PPAR) coactivator (PGC)-1. PGC-1α was discovered as a transcriptional regulator of UCP that plays a role in thermogenesis in adipose tissue.37 The expression of PGC-1α is increased on cellular ATP demand, including exercise, cold exposure, and fasting.38-41 PGC-1 is a coactivator of nuclear transcription factors including nuclear ...
  http://circres.ahajournals.org/content/102/4/401.full
*  Plus it
We investigated the biological activity of a novel thiazolidinedione (TZD) derivative, KRP-297, and the molecular basis of this activity. When administered to obese Zucker fatty rats (obese rats) at 10 mg/kg for 2 weeks, KRP-297, unlike BRL-49,653, restored reduced lipid oxidation, that is, CO2 and ketone body production from [14C]palmitic acid, in the liver by 39% (P , 0.05) and 57% (P , 0.01), respectively. KRP-297 was also significantly more effective than BRL-49,653 in the inhibition of enhanced lipogenesis and triglyceride accumulation in the liver. To understand the molecular basis of the biological effects of KRP-297, we examined the effect on peroxisome proliferator-activated receptor (PPAR) isoforms, which may play key roles in lipid metabolism. Unlike classical TZD derivatives, KRP-297 activated both PPAR-alpha and PPAR-gamma, with median effective concentrations of 1.0 and 0.8 micromol/l, ...
  http://diabetes.diabetesjournals.org/content/47/12/1841
*  The NCOR2 gene and its putative association with human ageing
NCOR2, also known as SMRT, is a transcriptional corepressor that maintains the transcriptional silencing of certain target genes. NCOR2 expression and its occupancy on peroxisome proliferator-activated receptor (PPAR) target gene promoters are increased with age in major metabolic tissues. Shifting its repressive activity towards PPARs, by selectively disabling one of its two major receptor-interacting domains, resulted in premature ageing in mice and related metabolic diseases accompanied by reduced mitochondrial function and antioxidant gene expression. Additionally, in a preliminary analysis, several human polymorphisms were found to be associated with type 2 diabetes [2196]. ...
  http://genomics.senescence.info/genes/entry.php?id=276