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151. Cholesterol induces fetal rat enterocyte death in culture

Author

Erica Paula Portioli Silva, Rozangela Verlengia, C.C. Kanunfre, Jussara Gazzola, M. G. Vecchia, and Rui Curi

Subjects
Male, Peroxisome proliferator-activated receptor gamma, PPARgamma, Physiology, Enterocyte, Immunology, Biophysics, Cell Culture Techniques, Apoptosis, Reductase, Biochemistry, chemistry.chemical_compound, Fetal enterocytes, Fetus, HMG-CoA, medicine, Animals, General Pharmacology, Toxicology and Pharmaceutics, Rats, Wistar, IEC-6 cells, lcsh:QH301-705.5, lcsh:R5-920, biology, Cholesterol, Reverse Transcriptase Polymerase Chain Reaction, General Neuroscience, Cell Biology, General Medicine, Peroxisome, Flow Cytometry, Molecular biology, Rats, Intestine, medicine.anatomical_structure, Enterocytes, chemistry, Microscopy, Fluorescence, lcsh:Biology (General), HMG-CoA reductase, biology.protein, Female, lcsh:Medicine (General)
Abstract

The effect of cholesterol on fetal rat enterocytes and IEC-6 cells (line originated from normal rat small intestine) was examined. Both cells were cultured in the presence of 20 to 80 microM cholesterol for up to 72 h. Apoptosis was determined by flow cytometric analysis and fluorescence microscopy. The expression of HMG-CoA reductase and peroxisome proliferator-activated receptor gamma (PPARgamma) was measured by RT-PCR. The addition of 20 microM cholesterol reduced enterocyte proliferation as early as 6 h of culture. Reduction of enterocyte proliferation by 28 and 41% was observed after 24 h of culture in the presence and absence of 10% fetal calf serum, respectively, with the effect lasting up to 72 h. Treatment of IEC-6 cells with cholesterol for 24 h raised the proportion of cells with fragmented DNA by 9.7% at 40 microM and by 20.8% at 80 microM. When the culture period was extended to 48 h, the effect of cholesterol was still more pronounced, with the percent of cells with fragmented DNA reaching 53.5% for 40 microM and 84.3% for 80 microM. Chromatin condensation of IEC-6 cells was observed after treatment with cholesterol even at 20 microM. Cholesterol did not affect HMG-CoA reductase expression. A dose-dependent increase in PPARgamma expression in fetal rat enterocytes was observed. The expression of PPAR-gamma was raised by 7- and 40-fold, in the presence and absence of fetal calf serum, respectively, with cholesterol at 80 mM. The apoptotic effect of cholesterol on enterocytes was possibly due to an increase in PPARgamma expression.

Published
2004

152. Transcriptional regulation of human CYP27 integrates retinoid, peroxisome proliferator-activated receptor, and liver X receptor signaling in macrophages

Author

Szilvia Benko, Laszlo Nagy, Sándor Molnár, Ralph Rühl, Sebastiano Calandra, Attila Szanto, R. Garuti, Ulf Diczfalusy, Hanna Larsson, Balint L. Balint, László Csiba, Istvan Szatmari, and Ibolya Fürtös

Subjects
PPARgamma, Transcription, Genetic, Arteriosclerosis, Receptors, Retinoic Acid, Receptors, Cytoplasmic and Nuclear, Biológiai tudományok, Biology, Retinoid X receptor, Ligands, Gene Expression Regulation, Enzymologic, Liver X receptor beta, Mice, Retinoids, Természettudományok, Animals, Humans, Liver X receptor, Promoter Regions, Genetic, Molecular Biology, CYP27 gene, Cells, Cultured, Liver X Receptors, Transcriptional Regulation, Retinoid X receptor alpha, Macrophages, Retinoic Acid Receptor alpha, human macrophage, liver X receptor alpha (LXRalpha), Liver X receptor alpha, Cell Biology, Cholesterol loading, Retinoid X receptor gamma, Orphan Nuclear Receptors, Hydroxycholesterols, Cell biology, DNA-Binding Proteins, Retinoid X Receptors, Biochemistry, Steroid Hydroxylases, Cholestanetriol 26-Monooxygenase, lipids (amino acids, peptides, and proteins), Institut für Ernährungswissenschaft, Peroxisome proliferator-activated receptor alpha, Retinoid X receptor beta, Signal Transduction, Transcription Factors
Abstract

Cholesterol uptake and efflux are key metabolic processes associated with macrophage physiology and atherosclerosis. Peroxisome proliferator-activated receptor gamma (PPARgamma) and liver X receptor alpha (LXRalpha) have been linked to the regulation of these processes. It remains to be identified how activation of these receptors is connected and regulated by endogenous lipid molecules. We identified CYP27, a p450 enzyme, as a link between retinoid, PPARgamma, and LXR signaling. We show that the human CYP27 gene is under coupled regulation by retinoids and ligands of PPARs via a PPAR-retinoic acid receptor response element in its promoter. Induction of the enzyme's expression results in an increased level of 27-hydroxycholesterol and upregulation of LXR-mediated processes. Upregulated CYP27 activity also leads to LXR-independent elimination of CYP27 metabolites as an alternative means of cholesterol efflux. Moreover, human macrophage-rich atherosclerotic lesions have an increased level of retinoid-, PPARgamma-, and LXR-regulated gene expression and also enhanced CYP27 levels. Our findings suggest that nuclear receptor-regulated CYP27 expression is likely to be a key integrator of retinoic acid receptor-PPARgamma-LXR signaling, relying on natural ligands and contributing to lipid metabolism in macrophages.

Published
2004

153. Die Bedeutung von 'Peroxisome Proliferator-Activated Receptors' in der Pathogenese von Gefäßwandläsionen und ihr Einfluß auf die Migration und Proliferation vaskulärer Zellen

Author

Götze, Stephan, Kroemer, H. K., and Hecker, M.

Subjects
PPARgamma, Signaltransduktion, XI 4400, 610 Medizin, vascular smooth muscle cells, ddc:610, 33 Medizin, Gefäßmuskelzellen, migration, signal transduction
Abstract

Die Migration und Proliferation vaskulärer Zellen spielt eine entscheidende Rolle in der Pathogenese atherosklerotischer Gefäßwandveränderungen und trägt zudem in hohem Maße zu restenosebedingten Komplikationen interventioneller Therapien der Atherosklerose bei. Dies bedingt ein großes Interesse an pharmakologischen Interventionsmöglichkeiten zur Prävention / Therapie atherosklerotischer und restenotischer vaskulärer Läsionen. Dabei kommen neben lokal applizierbaren Substanzgruppen insbesondere Pharmaka in Betracht, die bereits Anwendung zur Behandlung metabolischer Risikofaktoren kardiovaskulärer Erkrankungen finden. Hierzu gehören insbesondere die oralen Antidiabetika vom Typ der Thiazolidindeone, die als Liganden für den "Peroxisome Proliferator-Activated Receptor gamma" (PPARg) agieren. PPARs sind eine Gruppe neuer Regulatoren der Genexpression, für die in den vergangenen Jahren eine Reihe vaskulärer Wirkungen nachgewiesen wurden. Wir konnten zeigen, daß die Proliferation und Migration von Gefäßmuskelzellen durch PPARg-Liganden gehemmt wird. Untersuchungen zu den beteiligten Signalübertragungsschritten ergaben, daß die pharmakologische Aktivierung von PPARg in Gefäßmuskelzellen insbesondere die durch die Mitogen-aktivierten Protein Kinasen ERK1/2 vermittelte Signaltransduktion beeinflußt. Diesbezüglich haben wir nachgewiesen, daß PPARg in Gefäßmuskelzellen die mitogene Signaltransduktion via ERK1/2 MAPK -> Elk-1 -> c-fos und die chemotaktische Signalübertragung via ERK1/2 MAPK -> Ets-1 -> Matrixmetalloproteinase-9 hemmt. Wir konnten ferner zeigen, daß PPARg-Liganden die Endothelzellmigration hemmen, die durch die Neovaskularisation atherosklerotischer Plaques und der damit verbundenen erhöhten Vulnerabilität einer Plaqueruptur eine Rolle in der Pathobiologie der Atherosklerose spielt. Diese migrationshemmende Wirkung der PPARg-Liganden basiert vermutlich auf einer Inhibition der für die Endothelzellmigration erforderlichen Signaltransduktion über den PI3 Kinase -> Akt -> eNOS Pathway. Die Inhibition dieses Signalwegs könnte die Folge der von uns beobachteten PPARg-Ligand-induzierten Expression der Phosphatase PTEN sein, die den PI3K -> Akt Signalweg negativ reguliert und die Aktivierung und Phosphorylierung von Akt inhibiert. Somit haben PPARg-aktivierende Liganden eine wichtige Funktion in der Behandlung der metabolischen Hauptrisikofaktoren kardiovaskulärer Erkrankungen, spielen aber gleichzeitig eine vermutlich ebenso wichtige Rolle in der Protektion atherosklerotischer und restenosebedingter Gefäßwandveränderungen durch direkte vaskuläre Effekte., Migration and proliferation of vascular cells not only play an important role in the pathogenesis of atherosclerotic lesion formation, but also contribute to restenosis after therapeutic angioplasty. Therefore, pharmacological strategies for the prevention and/or treatment of atherosclerotic and restenotic vascular lesions are of great clinical interest. This involves substances that can be locally administered via stents, as well as agents that are already in clinical use for the treatment of metabolic risk factors. Among the latter, antidiabetic thiazolidinediones which function as ligands for the "peroxisome proliferator-activated receptor gamma" (PPARg), have been identified as promising drugs to target vascular lesion formation. PPARs constitute a group of novel regulators of gene expression, that exert several vascular effects. We report that vascular smooth muscle cell proliferation and migration is inhibited by PPARg-ligands. Investigating the signalling steps that are involved, we find that pharmacological activation of PPARg interferes with signal transduction through the mitogen-activated protein kinases ERK1/2 in vascular smooth muscle cells. We demonstrate that PPARg inhibits mitogenic signal transduction via ERK1/2 MAPK -> Elk-1 -> c-fos and also blocks chemotactic signalling through the ERK1/2 MAPK -> Ets-1 -> matrix metalloproteinase-9 pathway in vascular smooth muscle cells. We also showed that PPARg-ligands inhibit endothelial cell migration, which participates in the neovascularization of atherosclerotic plaques, thereby contributing to plaque destabilization and increased risk of plaque hemorrhage. This antimigratory action of PPARg-ligands results from an inhibition of signal transduction via PI3 Kinase -> Akt -> eNOS, a pathway that is crucial for endothelial cell migration. Since we observed a PPARg-ligand-induced upregulation of PTEN, a phosphatase that negatively regulates the PI3K -> Akt signalling pathway, this might constitute the mechanism by which PPARg-ligands inhibit endothelial cell migration. In conclusion, PPARg-activating ligands may provide a dual benefit in cardiovascular disease by ameliorating metabolic risk factors, as well as protecting the vasculature from atherosclerotic and restenotic alterations through direct vascular effects.

Published
2003

154. Die Bedeutung von 'Peroxisome Proliferator-Activated Receptors' in der Pathogenese von Gefäßwandläsionen und ihr Einfluß auf die Migration und Proliferation vaskulärer Zellen

Author

Kroemer, H. K., Hecker, M., Götze, Stephan, Kroemer, H. K., Hecker, M., and Götze, Stephan

Abstract

Die Migration und Proliferation vaskulärer Zellen spielt eine entscheidende Rolle in der Pathogenese atherosklerotischer Gefäßwandveränderungen und trägt zudem in hohem Maße zu restenosebedingten Komplikationen interventioneller Therapien der Atherosklerose bei. Dies bedingt ein großes Interesse an pharmakologischen Interventionsmöglichkeiten zur Prävention / Therapie atherosklerotischer und restenotischer vaskulärer Läsionen. Dabei kommen neben lokal applizierbaren Substanzgruppen insbesondere Pharmaka in Betracht, die bereits Anwendung zur Behandlung metabolischer Risikofaktoren kardiovaskulärer Erkrankungen finden. Hierzu gehören insbesondere die oralen Antidiabetika vom Typ der Thiazolidindeone, die als Liganden für den "Peroxisome Proliferator-Activated Receptor gamma" (PPARg) agieren. PPARs sind eine Gruppe neuer Regulatoren der Genexpression, für die in den vergangenen Jahren eine Reihe vaskulärer Wirkungen nachgewiesen wurden. Wir konnten zeigen, daß die Proliferation und Migration von Gefäßmuskelzellen durch PPARg-Liganden gehemmt wird. Untersuchungen zu den beteiligten Signalübertragungsschritten ergaben, daß die pharmakologische Aktivierung von PPARg in Gefäßmuskelzellen insbesondere die durch die Mitogen-aktivierten Protein Kinasen ERK1/2 vermittelte Signaltransduktion beeinflußt. Diesbezüglich haben wir nachgewiesen, daß PPARg in Gefäßmuskelzellen die mitogene Signaltransduktion via ERK1/2 MAPK -> Elk-1 -> c-fos und die chemotaktische Signalübertragung via ERK1/2 MAPK -> Ets-1 -> Matrixmetalloproteinase-9 hemmt. Wir konnten ferner zeigen, daß PPARg-Liganden die Endothelzellmigration hemmen, die durch die Neovaskularisation atherosklerotischer Plaques und der damit verbundenen erhöhten Vulnerabilität einer Plaqueruptur eine Rolle in der Pathobiologie der Atherosklerose spielt. Diese migrationshemmende Wirkung der PPARg-Liganden basiert vermutlich auf einer Inhibition der für die Endothelzellmigration erforderlichen Signaltransduktion über den PI3 Kinase, Migration and proliferation of vascular cells not only play an important role in the pathogenesis of atherosclerotic lesion formation, but also contribute to restenosis after therapeutic angioplasty. Therefore, pharmacological strategies for the prevention and/or treatment of atherosclerotic and restenotic vascular lesions are of great clinical interest. This involves substances that can be locally administered via stents, as well as agents that are already in clinical use for the treatment of metabolic risk factors. Among the latter, antidiabetic thiazolidinediones which function as ligands for the "peroxisome proliferator-activated receptor gamma" (PPARg), have been identified as promising drugs to target vascular lesion formation. PPARs constitute a group of novel regulators of gene expression, that exert several vascular effects. We report that vascular smooth muscle cell proliferation and migration is inhibited by PPARg-ligands. Investigating the signalling steps that are involved, we find that pharmacological activation of PPARg interferes with signal transduction through the mitogen-activated protein kinases ERK1/2 in vascular smooth muscle cells. We demonstrate that PPARg inhibits mitogenic signal transduction via ERK1/2 MAPK -> Elk-1 -> c-fos and also blocks chemotactic signalling through the ERK1/2 MAPK -> Ets-1 -> matrix metalloproteinase-9 pathway in vascular smooth muscle cells. We also showed that PPARg-ligands inhibit endothelial cell migration, which participates in the neovascularization of atherosclerotic plaques, thereby contributing to plaque destabilization and increased risk of plaque hemorrhage. This antimigratory action of PPARg-ligands results from an inhibition of signal transduction via PI3 Kinase -> Akt -> eNOS, a pathway that is crucial for endothelial cell migration. Since we observed a PPARg-ligand-induced upregulation of PTEN, a phosphatase that negatively regulates the PI3K -> Akt signalling pathway, this might constitute the mechani

Published
2003

155. FAM3A mediates PPARγ's protection in liver ischemia-reperfusion injury by activating Akt survival pathway and repressing inflammation and oxidative stress.

Author

Chen Z, Wang J, Yang W, Chen J, Meng Y, Geng B, Cui Q, and Yang J

Subjects
Animals, Apoptosis, Cell Survival, Cytokines genetics, Disease Models, Animal, Disease Progression, Gene Expression, Hepatocytes metabolism, Liver Diseases pathology, Liver Function Tests, Male, Mice, Mice, Knockout, Protein Transport drug effects, Reperfusion Injury pathology, Rosiglitazone, Thiazolidinediones pharmacology, Cytokines metabolism, Liver Diseases metabolism, Oxidative Stress drug effects, PPAR gamma metabolism, Proto-Oncogene Proteins c-akt metabolism, Reperfusion Injury metabolism, Signal Transduction drug effects
Abstract

FAM3A is a novel mitochondrial protein, and its biological function remains largely unknown. This study determined the role and mechanism of FAM3A in liver ischemia-reperfusion injury (IRI). In mouse liver after IRI, FAM3A expression was increased. FAM3A-deficient mice exhibited exaggerated liver damage with increased serum levels of AST, ALT, MPO, MDA and oxidative stress when compared with WT mice after liver IRI. FAM3A-deficient mouse livers had a decrease in ATP content, Akt activity and anti-apoptotic protein expression with an increase in apoptotic protein expression, inflammation and oxidative stress when compared WT mouse livers after IRI. Rosiglitazone pretreatment protected against liver IRI in wild type mice but not in FAM3A-deficient mice. In cultured hepatocytes, FAM3A overexpression protected against, whereas FAM3A deficiency exaggerated oxidative stress-induced cell death. FAM3A upregulation or FAM3A overexpression inhibited hypoxia/reoxygenation-induced activation of apoptotic gene and hepatocyte death in P2 receptor-dependent manner. FAM3A deficiency blunted rosiglitazone's beneficial effects on Akt activation and cell survival in cultured hepatocytes. Collectively, FAM3A protects against liver IRI by activating Akt survival pathways, repressing inflammation and attenuating oxidative stress. Moreover, the protective effects of PPARγ agonist(s) on liver IRI are dependent on FAM3A-ATP-Akt pathway.

Published
2017
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156. The role of retinaldehyde and PPARgamma signaling in systemic lupus erythematosus

Author

Su, Shi

Subjects
Biology, PPARgamma, Retinaldehyde, Systemic Lupus Erythematosus
Abstract

Systemic Lupus Erythematosus (SLE) is an autoimmune disease with chronic inflammation affecting multiple organ systems, as well as accelerated atherosclerosis as a major complication. Prior studies by our lab have shown beneficial effects of PPARgamma agonists towards preventing SLE in two different mouse models: the well-established lupus mouse model, MRL.lpr, and the gld.apoE^-/- model of accelerated lupus and atherosclerosis. Retinaldehyde is a retinoic acid precursor that has recently been shown to inhibit PPARgamma signaling in adipose tissue. We proposed that abnormal accumulation of retinaldehyde in lupus promotes autoimmunity by inhibition of PPARgamma signaling. We measured the serum retinaldehyde levels in both lupus mouse models using reversed-phase high-performance liquid chromatography. We also examined the mRNA expressions of genes involved in retinaldehyde metabolism and PPARgamma signaling in white adipose tissues using real-time quantitative PCR. We observed a higher level of circulating retinaldehyde in the MRL.lpr mouse model on a chow diet. The circulating retinaldehyde levels in both .gld.apoE^-/- and C57 increased when maintained on a high-cholesterol Western diet. Within visceral and subcuntaneous adipose tissue, we saw several changes to expression of the genes responsible for retinaldehyde synthesis and catabolism, however further study is required to definitively assess the role of these genes. Importantly, the expression levels of genes involved in PPARgamma signaling decreased in the subcutaneous fat of gld.apoE^-/- mice on a Western diet. Our data suggest that retinaldehyde may play a role in SLE pathogenesis and could be a potential therapeutic target for SLE.

Published
2014

157. PPARɣ Activation Rapidly Ameliorates Amyloid Pathology and Restores Cognition in a Mouse Model of Alzheimer’s Disease

Author

Mandrekar-Colucci, Shweta Dilip

Subjects
Neurosciences, Alzheimer's Disease, Microglia, PPARgamma
Abstract

Alzheimer’s disease (AD) is a chronic neurodegenerative disease characterized by the progressive loss of cognition and memory. The pathological hallmarks of AD include extracellular amyloid deposits and intra-neuronal neurofibrillary tangles. Progression of the disease is associated with a disruption of Aβ homeostasis and accumulation and deposition of Aβ in the brain parenchyma, initiating a robust microglial-mediated immune response that leads to the production of pro-inflammatory cytokines, chemokines and reactive nitrogen and oxygen species which are deleterious to the CNS. Despite the abundance of activated microglia surrounding plaques, they are inefficient in clearing fibrillar Aβ deposits. It is thought that activating mechanisms that facilitate Aβ clearance will alleviate disease related pathophysiology and be of great therapeutic utility for the treatment of Alzheimer’s disease.The peroxisome proliferator activated receptor-ɣ (PPARɣ), is a ligand activated nuclear receptor, which regulates lipid and glucose homeostasis in the body and exhibits potent anti-inflammatory actions. Activation of PPARγ has been shown to reduce brain Aβ levels and ameliorate AD related cognitive deficits in animal models of AD. However, the mechanisms through which PPARγ attenuates AD related pathophysiology have yet to be elucidated. We have shown that activation of another nuclear receptor, LXRα, facilitates the proteolytic degradation of Aβ in an ApoE-dependent mechanism through induction of target genes, ABCA1 and ApoE. ABCA1 regulates cholesterol efflux via lipidation of ApoE and this process augments the degradation of soluble Aβ species. Importantly, PPARγ activation induces the expression of LXRα and its targets ApoE and ABCA1, metabolically linking these pathways.We demonstrate that PPARɣ activation using the synthetic agonist, Pioglitazone (Actos™) enhances the proteolytic degradation of Aβ in microglia and astrocytes by utilizing the PPAR-LXR-ApoE linked pathway in the brain. PPARɣ mediated intracellular degradation of Aβ is dependent on expression of ApoE and LXR. Furthermore, an acute (9 day) treatment of APP/PS1 mice with pioglitazone, rapidly increased brain levels of ABCA1 and ApoE, decreased amyloid deposition and ameliorated AD-related cognitive deficits. The reduction in plaque deposition was paralleled with an increase in amyloid-laden microglia and astrocytes in the parenchyma of treated animals. Significantly, pioglitazone treatment of APP/PS1 animals polarized CNS microglia from a “classical” to an “alternative” activation state, reducing glial activation, re-engaging the phagocytic machinery and facilitating the clearance of fibrillar Aβ deposits. Together our data demonstrates an important role for PPARɣ activation in facilitating the clearance of both soluble and fibrillar species of Aβ and provides a mechanistic explanation for how PPARɣ agonists reduce AD-related pathophysiology.

Published
2011

158. PPAR-gamma in inflammation.

Author

Ivashchenko, Christine Y.

Subjects
Gamma, Inflammation, Ppar, Ppargamma, Thiazolidinediones
Abstract

The ligand-dependent transcription factor, peroxisome proliferator activated receptor, (PPAR-gamma), is a member of the nuclear hormone receptor superfamily and a target of antidiabetic thiazolidinediones (TZDs). Initially characterized for its effects in glucose and lipid metabolism, PPAR-gamma activation has been shown to play critical roles in the inhibition of inflammatory vascular diseases such as atherosclerosis. Since PPAR-gamma agonists have receptor-independent actions, knockout studies are required to determine whether PPAR-gamma is necessary for the inhibitory effects of the PPAR-gamma agonists. Due to the pleiotropic effects of the PPAR-gamma activation, establishing which cell types are responsible for the anti-inflammatory effects observed in whole organism studies is difficult without the use of the cell-specific knockouts. To unravel the complex role of PPAR-gamma in inflammation and to begin categorizing relative contributions of PPAR-gamma activity in different cell types, we created two PPAR-gamma knockout models: pancreatic epithelial cell knockout and vascular endothelial cell knockout. These knockout models not only provided insight into the important role PPAR-gamma plays in the control of cell inflammation but also showed that TZDs act directly through PPAR-gamma in suppressing inflammation in an in vivo model of acute pancreatitis and in an in vitro models of endothelial cell inflammation. We show that PPAR-gamma in acinar cells, and not in inflammatory cells, is the target of the TZD anti-inflammatory activity in the model of acute pancreatitis. In vascular endothelial cells, PPAR-gamma is required for TZD activity and PPAR-gamma activation inhibits the function of a pro-inflammatory transcription factor NF-kappaB by decreasing the formation of functional transcriptional complexes at the promoters of NF-kappaB target genes.

Published
2007

159. PPAR-gamma: A multifaceted transcription factor important in diabetes, cardiovascular disease, and cancer.

Author

Duan, Shengzhong

Subjects
Cancer, Cardiovascular Disease, Diabetes, Important, Multifaceted, Ppar-gamma, Ppargamma, Transcription Factor
Abstract

Peroxisome proliferator-activated receptor gamma (PPAR-gamma) is a nutrient-sensing transcription factor that associates with cardiovascular diseases and metabolic disorders. Its agonists, the thiazolidinediones (TZDs), are clinically used to treat type 2 diabetes. This thesis investigated the multifaceted functions of PPAR-gamma and the pharmacology of TZDs in insulin sensitivity, glucose homeostasis, adipogenesis, blood pressure regulation, tumorigenesis, and cardiac growth. We rescued the embryonic lethality of generalized PPAR-gamma deficiency using Cre-LoxP technology to preserve PPAR-gamma expression in the placenta (MORE-PGKO mice). These mice demonstrated that PPAR-gamma is required to maintain normal adiposity, insulin sensitivity, and blood pressure. Administration of rosiglitazone, a TZD, to these PPAR-gamma deficiency mice improved glucose homeostasis in both males and females. In females, rosiglitazone stimulated fat growth and was sufficient to improve insulin sensitivity. Vaspin, but not likely leptin or adiponectin, is a candidate adipokine that is responsible for this insulin-sensitizing effect. In males, glucose homeostasis was improved independently of adipose tissue and insulin-sensitivity likely by improving beta-cell function. Surprisingly, rosiglitazone treatment of male MORE-PGKO mice led to the development liver tumors, suggesting a tumor suppressor function of PPAR-gamma. To directly determine the role of PPAR-gamma in cardiac growth, we developed a cardiomyocyte-specific PPAR-gamma knockout (CM-PGKO) mouse model. Cardiomyocyte PPAR-gamma was required to suppress cardiac growth, embryonic gene expression, and nuclear-factor-kappa-B activity in vivo. Rosiglitazone induced cardiac hypertrophy at least partially independent of PPAR-gamma in cardiomyocytes and through different mechanisms from CM-PGKO. These data may provide guidance for designing new drugs with fewer cardiac side effects. In order to distinguish TZDs' intrinsic effects on cardiomyocytes from their blood pressure-lowering effects, we monitored pressure overload (POL) and found that systolic pressure at later stages was the major determinant of cardiac hypertrophy. In contrast to pioglitazone and troglitazone, rosiglitazone did not inhibit POL-induced cardiac hypertrophy. Future studies comparing multiple TZDs are needed to understand the pharmacology of this effect and to explore the role of PPAR-gamma in POL-induced cardiac hypertrophy.

Published
2006

160. Human Bone Marrow Mesenchymal Stem Cell Behaviors on PCL/Gelatin Nanofibrous Scaffolds Modified with A Collagen IV-Derived RGD-Containing Peptide.

Author

Mota A, Sahebghadam Lotfi A, Barzin J, Hatam M, Adibi B, Khalaj Z, and Massumi M

Abstract

Objective: We introduce an RGD (Arg-Gly-Asp)-containing peptide of collagen IV origin that possesses potent cell adhesion and proliferation properties., Materials and Methods: In this experimental study, the peptide was immobilized on an electrospun nanofibrous polycaprolactone/gelatin (PCL/Gel) hybrid scaffold by a chemical bonding approach to improve cell adhesion properties of the scaffold. An iodine-modified phenylalanine was introduced in the peptide to track the immobilization process. Native and modified scaffolds were characterized with scanning electronmicroscopy (SEM) and fourier transform infrared spectroscopy (FTIR). We studied the osteogenic and adipogenic differentiation potential of human bone marrow-derived mesenchymal stem cells (hBMSCs). In addition, cell adhesion and proliferation behaviors of hBMSCs on native and peptide modified scaffolds were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and 4',6-diamidino-2-phenylindole (DAPI) staining, and the results compared with tissue culture plate, as the control., Results: FTIR results showed that the peptide successfully immobilized on the scaffold.MTT assay and DAPI staining results indicated that peptide immobilization had a dramatic effect on cell adhesion and proliferation., Conclusion: This peptide modified nanofibrous scaffold can be a promising biomaterial for tissue engineering and regenerative medicine with the use of hBMSCs., (Copyright © 2014. Published by Royan Institute (ACECR). Full text is avalible in: www.celljournal.org.)

Published
2014

161. C-reactive Protein in Patients with Metastatic Clear Cell Renal Carcinoma: An Important Biomarker for Tumor-associated Inflammation.

Author

Reichle A, Grassinger J, Bross K, Wilke J, Suedhoff T, Walter B, Wieland WF, Berand A, and Andreesen R

Abstract

Two consecutive multi-center phase II trials were designed to prove the hypothesis, whether therapeutic modeling of tumor-associated inflammatory processes could result in improved tumor response.Therapy in both trials consisted of low-dose capecitabine 1g/m2 twice daily p.o. for 14 days, every 3 weeks, day 1+, and rofecoxib 25 mg daily p.o., day 1+ (from 11/04 etoricoxib 60 mg daily instead) plus pioglitazone 60 mg daily p.o., day 1+. In study II low-dose IFN-alpha 4.5 MU sc. three times a week, week 1+, was added until disease progression.Eighteen, and 33 patients, respectively, with clear cell renal carcinoma and progressive disease were enrolled. Objective response (48%) was exclusively observed in study II (PR 35%, CR 13%), and paralleled by a strong CRP response after 4 weeks on treatment, p = 0.0005, in all 29 pts (100%) with elevated CRP levels. Median progression-free survival could be more than doubled from a median of 4.7 months (95% CI, 1.0 to 10.4) to 11.5 months (6.8 to 16.2) in study II, p = 0.00001. Median overall survival of population II was 26 months.Efficacious negative regulation of tumor-associated inflammation by transcription modulators may result in a steep increase of tumor response and survival.

Published
2007

162. THE STROMAL ROLE OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR GAMMA IN BREAST TUMOURIGENESIS

Author

Queen's University (Kingston, Ont.). Theses (Queen's University (Kingston, Ont.)), Skelhorne-Gross, GRAHAM, Queen's University (Kingston, Ont.). Theses (Queen's University (Kingston, Ont.)), and Skelhorne-Gross, GRAHAM

Abstract

Breast cancer is the most commonly diagnosed female cancer, and kills 1 in 30 Canadian women, mostly from metastatic disease. Previous studies showed PPARγ decreases breast cancer progression, but due to the many mammary gland-associated cell types expressing PPARγ, each with unique signal patterns, the mechanisms required clarification. To define the mammary stromal role of PPARγ during breast tumourigenesis, cell-type targeted PPARγ knockout (KO) mice were generated, and studied using both chemical carcinogen (DMBA) and multi-risk factor DMBA + protumourigenic high fat diet (ProHF) models. PPARγ adipocyte targeted KO mice (PPARγ-A KO) were more susceptible to DMBA and DMBA+ProHF-induced mammary tumourigenesis than wild-type (PPARγ-WT) controls. In both studies, PPARγ-A KO mice had increased mammary tumour incidences and decreased latency. PPARγ-A KOs also developed more ovarian tumours when treated with DMBA+ProHF. Dietary supplementation with the PPARγ activator rosiglitazone (ROSI) rescued tumourigenic phenotypes in PPARγ-WTs more so than PPARγ-A KOs. Mechanistic studies unveiled untreated PPARγ-A KOs had significantly decreased BRCA1 expression in mammary stromal adipocytes, decreased circulating IL-2, IL-13 and MIP-1α, and increased serum leptin. BRCA1 regulates aromatase in adipocytes, IL-2, IL-13 and MIP-1α stimulate immune surveillance, and leptin promotes tumour cell proliferation and angiogenesis. These novel findings suggest that loss of PPARγ in mammary stromal adipocytes exerts both local and systemic protumourigenic signaling changes contributing to breast and ovarian tumourigenesis, and that use of ROSI may be beneficial to some patients. Since human use of ROSI is limited due to peripheral edema, which may stem from vascular endothelial cell (VEC) effects, PPARγ-VEC KO mice were used to unravel the mechanisms. In contrast to PPARγ-WTs, PPARγ-VEC KOs resisted extracellular fluid increases and plasma volume expansion in response to ROSI. FAK and VE-ca, Thesis (Ph.D, Pathology & Molecular Medicine) -- Queen's University, 2014-08-01 12:44:14.23

163. Die Untersuchung von PPARgamma-abhängigen sowie -unabhängigen Mechanismen der Apoptose-Induktion in T-Zellen und deren Relevanz bei der Pathogenese der Sepsis

Author

Soller, Mathias and Soller, Mathias

Abstract

Sepsis ist eine lebensbedrohliche Krankheit und eine der häufigsten Todesursachen auf Intensiv-Stationen. Eine der Hauptursachen für die Schwere dieser Krankheit ist die Lymphopenie, d. h. die apoptotische Depletion von Lymphozyten, die vor allem in der späten hypo-inflammatorischen Phase der Sepsis auftritt. Die dafür verantwortlichen Signalwege sind jedoch nicht im Detail geklärt. Die Liganden-vermittelte Aktivierung von PPARgamma (‚peroxisome proliferator activated receptor gamma’), einem wichtigen Regulator der Immunantwort, führt zur Apoptose in aktivierten T-Zellen. Daher postulierte ich, dass die PPARgamma-vermittelte Apoptose in T-Zellen zur Lymphopenie während der Sepsis beiträgt. Hierbei konnte ich zeigen, dass T-Zellen aus dem peripheren Blut von Sepsis-Patienten eine stark erhöhte PPARgamma-mRNA-Expression zeigten und in vitro stark erhöhte Apoptoseraten infolge einer Liganden-vermittelten PPARgamma-Aktivierung aufwiesen. Die hierfür erforderlichen PPARgamma-Liganden lagen im Plasma von Sepsis-Patienten vor. D. h. die PPARgamma-vermittelte Apoptose in T-Zellen könnte zur nachgewiesenen Lymphopenie während der Sepsis beitragen. Aufgrund der anti-inflammatorischen Wirkung von PPARgamma könnte dessen gezielte Aktivierung in der frühen hyper-inflammatorischen Phase durch Thiazolidindione (TZDs) als synthetische PPARgamma-Aktivatoren therapeutisch interessant sein. Da diese jedoch auch auf PPARgamma-unabhängigen Wegen den Zelltod in T-Zellen induzieren können, war es essentiell, die dafür verantwortlichen Signalwege zu klären. Dabei konnte ich feststellen, dass Ciglitazon Nekrose und Troglitazon Apoptose auf PPARgamma-unabhängigen Wegen bereits nach 4 h in Jurkat T-Zellen induzierten, wohingegen Rosiglitazon keinen Einfluss auf den Zelltod hatte. Die Inkubation der TZDs führte zur Produktion von reaktiven Sauerstoffspezies, welche eine wichtige Rolle bei der Ciglitazon-induzierten Nekrose, jedoch nur marginal bei der Troglitazon-induzierten Apoptose spielten., Sepsis is the most common cause of death in intensive care units. Lymphopenia, mainly caused by apoptotic depletion of T cells, occurs during the hypo-inflammatory phase of sepsis and is one of the main reasons for poor outcome of this disease. However, pathways leading to lymphopenia are not identified in detail. Studies in mice and human cells suggested a role of the peroxisome proliferator-activated receptor gamma (PPARgamma), a major regulator of adaptive immune response, in provoking apoptosis in activated T lymphocytes. Therefore, I postulated that activation of PPARgamma might contribute to T cell death during sepsis leading to lymphocyte loss in sepsis. In my study, I observed strong PPARgamma up-regulation in T cells of septic patients. In contrast to controls, PPARgamma expressing cells from septic patients responded with apoptosis following PPARgamma activation in vitro. PPARgamma ligands, responsible for PPARgamma activation in T cells in vivo were identified in sera of septic patients. Therefore, apoptosis in T cells due to PPARgamma activation may contribute to lymphopenia occurring during the hypo-inflammatory phase of sepsis. Since PPARgamma also provokes an anti-inflammatory immune response its activation during the hyper-inflammatory phase of sepsis may represent a potential therapy approach. Thiazolidinediones (TZDs) as PPARgamma activators are of potential interest since they are already therapeutically used as insulin sensitizers. However, besides therapeutical benefits, TZDs also act in a PPARgamma-independent manner thereby inducing cell death which was the focus in my further studies. In Jurkat T cells, ciglitazone and troglitazone provoked rapid and dose-dependent cell death, whereas rosiglitazone did not alter cell viability. I found induction of apoptosis by troglitazone, whereas ciglitazone caused necrosis in a PPARgamma-independent manner. Because pre-incubation with reactive oxygen species (ROS) scavengers significantly inhibited ciglit

164. Effects of PPARγ ligands on vascular tone

Author

Salvatore Salomone and Filippo Drago

Subjects
medicine.medical_specialty, PPARgamma, Endothelium, Vasodilation, Context (language use), Biology, Pharmacology, Ligands, Muscle, Smooth, Vascular, In vivo, Internal medicine, Thiazolidinediones, Vascular tone, medicine, Humans, Hypoglycemic Agents, Receptor, Transcription factor, Lipid metabolism, General Medicine, PPAR gamma, Endocrinology, medicine.anatomical_structure, Gene Expression Regulation, Cardiovascular Diseases, Nitric Oxide Synthase, Rosiglitazone, medicine.drug
Abstract

Peroxisome Proliferator-Activated Receptor γ (PPARγ), originally described as a transcription factor for genes of carbohydrate and lipid metabolism, has been more recently studied in the context of cardiovascular pathophysiology. Here, we review the available data on PPARγ ligands as modulator of vascular tone. PPARγ ligands include: thiazolidinediones (used in the treatment of type 2 diabetes mellitus), glitazars (bind and activate both PPARγ and PPARα), and other experimental drugs (still in development) that exploit the chemistry of thiazolidinediones as a scaffold for PPARγ-independent pharmacological properties. In this review, we examine both short (mostly from in vitro data)- and long (mostly from in vivo data)-term effects of PPARγ ligands that extends from PPARγ-independent vascular effects to PPARγ-dependent gene expression. Because endothelium is a master regulator of vascular tone, we have attempted to differentiate between endothelium-dependent and endothelium-independent effects of PPARγ ligands. Based on available data, we conclude that PPARγ ligands appear to influence vascular tone in different experimental paradigms, most often in terms of vasodilatation (potentially increasing blood flow to some tissues). These effects on vascular tone, although potentially beneficial, must be weighed against specific cardiovascular warnings that may apply to some drugs, such as rosiglitazone.

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