Peroxisome proliferator-activated receptor-γ ligands induce heme oxygenase-1 in lung fibroblasts by a PPARγ-independent, glutathione-dependent mechanism

Ferguson, Heather E.; Thatcher, Thomas H.; Olsen, Keith C.; García-Bates, Tatiana M.; Baglole, Carolyn J.; Kottmann, R. Matthew; Strong, Emily; Phipps, Richard P.; Sime, Patricia J.

doi:10.1152/ajplung.00148.2009

Cited by 45 publications

(46 citation statements)

References 61 publications

(93 reference statements)

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“…We have previously shown that CDDO potently up-regulates expression of oxidative stressresponse proteins in a glutathionedependent manner and that NAC inhibits this up-regulation (29,41). Here, we show that NAC blocks up-regulation of HO-1 but does not inhibit the ability of CDDO to reduce TG2 expression ( Figure 5C).…”

Section: Discussionsupporting

confidence: 54%

“…Cells were incubated with the dominantnegative (DN) PPARg lentiviral vector (29) and polybrene in serum-free media for 2 hours. Growth media was then added, and transfection was assessed by green fluorescence protein (GFP) fluorescence 48 hours later.…”

Section: Pparg Lentivirusmentioning

confidence: 99%

“…We previously demonstrated that CDDO and 15d-PGJ 2 up-regulate expression of antioxidant proteins in a glutathione-dependent manner (29). Therefore, to determine if the decrease in TG2 caused by CDDO treatment was due to activation of this pathway, HLFs were pretreated with NAC.…”

Section: An Electrophilic Carbon Is Necessary To Decrease Tg2 Expressionmentioning

confidence: 99%

“…Therefore, to determine if the decrease in TG2 caused by CDDO treatment was due to activation of this pathway, HLFs were pretreated with NAC. NAC is an antioxidant and a precursor for the intracellular antioxidant glutathione (29). The effectiveness of NAC in reducing antioxidant pathway activation is demonstrated by examination of the level of expression of HO-1, a protein induced by oxidative stress.…”

Section: An Electrophilic Carbon Is Necessary To Decrease Tg2 Expressionmentioning

confidence: 99%

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Inhibition of Transglutaminase 2, a Novel Target for Pulmonary Fibrosis, by Two Small Electrophilic Molecules

Olsen

Epa²,

Kulkarni

et al. 2014

Am J Respir Cell Mol Biol

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Idiopathic pulmonary fibrosis (IPF) is characterized by progressive fibrotic destruction of normal lung architecture. Due to a lack of effective treatment options, new treatment approaches are needed. We previously identified transglutaminase (TG)2, a multifunctional protein expressed by human lung fibroblasts (HLFs), as a positive driver of fibrosis. TG2 catalyzes crosslinking of extracellular matrix proteins, enhances cell binding to fibronectin and integrin, and promotes fibronectin expression. We investigated whether the small electrophilic molecules 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) and 15-deoxy-delta-12,14-prostaglandin J 2 (15d-PGJ 2 ) inhibit the expression and profibrotic functions of TG2. CDDO and 15d-PGJ 2 reduced expression of TG2 mRNA and protein in primary HLFs from control donors and donors with IPF. CDDO and 15d-PGJ 2 also decreased the in vitro profibrotic effector functions of HLFs including collagen gel contraction and cell migration. The decrease in TG2 expression did not occur through activation of the peroxisome proliferator activated receptor g or generation of reactive oxidative species. CDDO and 15d-PGJ 2 inhibited the extracellular signal-regulated kinase pathway, resulting in the suppression of TG2 expression. This is the first study to show that small electrophilic compounds inhibit the expression and profibrotic effector functions of TG2, a key promoter of fibrosis. These studies identify new and important antifibrotic activities of these two small molecules, which could lead to new treatments for fibrotic lung disease.

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Section: Discussionsupporting

confidence: 54%

Section: Pparg Lentivirusmentioning

confidence: 99%

Section: An Electrophilic Carbon Is Necessary To Decrease Tg2 Expressionmentioning

confidence: 99%

Section: An Electrophilic Carbon Is Necessary To Decrease Tg2 Expressionmentioning

confidence: 99%

See 2 more Smart Citations

Inhibition of Transglutaminase 2, a Novel Target for Pulmonary Fibrosis, by Two Small Electrophilic Molecules

Olsen

Epa²,

Kulkarni

et al. 2014

Am J Respir Cell Mol Biol

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“…Thus, to see a beneficial effect of rosiglitazone on the sFlt-1/VEGF balance (as a consequence of alterations in placental HO-1 expression) it may be necessary to implement treatment at the point of surgical intervention (ie, RUPP surgery on GD14) as per cobalt (III) protoporphyrin IX chloride treatment. However, although rosiglitazone has been shown to upregulate HO-1 expression in both vascular smooth muscle and endothelial cells 10 it failed to do so in lung fibroblasts, 38 which may suggest a cell-specific effect that does not extend to the most abundant placental cell type, the trophoblast. Thus, in the present study, the beneficial effects of rosiglitazone, in terms of both vascular function and blood pressure, may simply be mediated by direct modulation of endothelial HO-1 activity, because these effects were abrogated by the HO-1 activity inhibitor SnPP.…”

Section: Discussionmentioning

confidence: 99%

Peroxisome Proliferator-Activated Receptor-γ as a Potential Therapeutic Target in the Treatment of Preeclampsia

et al. 2011

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Abstract-Preeclampsia is a multisystemic disorder of pregnancy characterized by hypertension, proteinuria, and maternal endothelial dysfunction. It is a major cause of maternal and perinatal morbidity and mortality and is thought to be attributable, in part, to inadequate trophoblast invasion. Peroxisome proliferator-activated receptor-␥ (PPAR-␥) is a ligand-activated transcription factor expressed in trophoblasts, and the vasculature of which activation has been shown to improve endothelium-dependent vasodilatation in hypertensive conditions. We investigated the effects of the administration of a PPAR-␥ agonist using the reduced uterine perfusion pressure (RUPP) rat model of preeclampsia. The selective PPAR-␥ agonist, rosiglitazone, was administered to pregnant rats that had undergone RUPP surgery. To investigate whether any observed beneficial effects of PPAR-␥ activation were mediated by the antioxidant enzyme, heme oxygenase 1, rosiglitazone was administered in combination with the heme oxygenase 1 inhibitor tinprotoporphyrin IX. RUPP rats were characterized by hypertension, endothelial dysfunction, and elevated microalbumin:creatinine ratios. Rosiglitazone administration ameliorated hypertension, improved vascular function, and reduced the elevated microalbumin:creatinine ratio in RUPP rats. With the exception of microalbumin:creatinine ratio, these beneficial effects were abrogated in the presence of the heme oxygenase 1 inhibitor. Administration of a PPAR-␥ agonist prevented the development of several of the pathophysiological characteristics associated with the RUPP model of preeclampsia, via a heme oxygenase 1-dependent pathway. The findings from this study provide further insight into the underlying etiology of preeclampsia and a potential therapeutic target for the treatment of preeclampsia. (Hypertension. 2011;58:280-286.) • Online Data SupplementKey Words: peroxisome proliferator-activated receptor-␥ Ⅲ preeclampsia Ⅲ reduced uterine perfusion pressure Ⅲ hypertension Ⅲ heme oxygenase 1 Ⅲ vascular dysfunction P reeclampsia is a major cause of maternal and perinatal morbidity and mortality worldwide, causing Ϸ15% of all direct maternal deaths and mediating a 5-fold increase in perinatal mortality. 1 Although the underlying etiology of preeclampsia is poorly understood, it is characterized by a relatively hypoperfused placenta, which stimulates the maternal response manifesting as hypertension, vascular dysfunction, alterations in platelet aggregation, and a pro-oxidant state. 2 There is currently no effective pharmacological intervention available for the treatment of preeclampsia, and, consequently, pregnancies are often delivered preterm for maternal benefit, imposing the challenges of iatrogenic prematurity on the fetus. 3 Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that regulate the expression of a number of genes involved in cell differentiation and proliferation. 4 PPAR-␥ plays a predominant role in normal vascular function 5 and in the differ...

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Inhibition of neointimal formation by trans‐resveratrol: Role of phosphatidyl inositol 3‐kinase‐dependent Nrf2 activation in heme oxygenase‐1 induction

Kim

Lim

Lee

et al. 2010

Molecular Nutrition Food Res

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Neointima, defined as abnormal growth of the intimal layer of blood vessels, is believed to be a critical event in the development of vascular occlusive disease. Although resveratrol's inhibitory effects on proliferation and migration of vascular smooth muscle cells has been reported, its activity on neointimal formation is still unclear. Oral administration of trans-resveratrol significantly suppressed intimal hyperplasia in a wire-injured femoral artery mouse model. In cultured vascular smooth muscle cells, trans-resveratrol inhibited platelet-derived growth factor-stimulated DNA synthesis and cell proliferation with down-regulation of cyclin D and pRB. Moreover, platelet-derived growth factor-induced production of reactive oxygen species was inhibited by trans-resveratrol and the compound induced heme oxygenase-1 (HO-1). The anti-proliferative activity of trans-resveratrol was reversed by an HO-1 inhibitor, ZnPPIX. Subcellular fractionation and reporter gene analyses revealed that trans-resveratrol increased the level of nuclear Nrf2 and antioxidant response element reporter activity, and that these were essential for the induction of HO-1. Trans-resveratrol also enhanced the activities of phosphatidyl inositol 3-kinase and extracellular signal regulated kinase, and phosphatidyl inositol 3-kinase was required for Nrf2/antioxidant response element-dependent HO-1 induction. These data have significant implications for the elucidation of the pharmacological mechanism by which trans-resveratrol prevents vascular occlusive diseases.

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Peroxisome proliferator-activated receptor-γ ligands induce heme oxygenase-1 in lung fibroblasts by a PPARγ-independent, glutathione-dependent mechanism

Cited by 45 publications

References 61 publications

Inhibition of Transglutaminase 2, a Novel Target for Pulmonary Fibrosis, by Two Small Electrophilic Molecules

Inhibition of Transglutaminase 2, a Novel Target for Pulmonary Fibrosis, by Two Small Electrophilic Molecules

Peroxisome Proliferator-Activated Receptor-γ as a Potential Therapeutic Target in the Treatment of Preeclampsia

Inhibition of neointimal formation by trans‐resveratrol: Role of phosphatidyl inositol 3‐kinase‐dependent Nrf2 activation in heme oxygenase‐1 induction

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