PPARγ Activation in Human Endothelial Cells Increases Plasminogen Activator Inhibitor Type-1 Expression

Marx, Nikolaus; Bourcier, Todd; Sukhova, Galina K.; Libby, Peter; Plutzky, Jorge

doi:10.1161/01.atv.19.3.546

Cited by 345 publications

(221 citation statements)

References 51 publications

Supporting

Mentioning

212

Contrasting

Unclassified

Order By: Relevance

“…In vascular endothelium, PPAR␥ functions to increase Cu/Zn superoxide dismutase 33 and plasminogen activator inhibitor-1 expression 8 and inhibit cytokine-induced monocyte chemotactic protein-1 production, 34 leukocyte-endothelial interactions, 10 angiogenesis, 11 and thrombin-induced endothelin-1 production. 9 Taken together, these reports suggest that PPAR␥ plays an important role in endothelial biology and the pathogenesis of vascular disease.…”

Section: Discussionmentioning

confidence: 99%

“…12 The expression of PPARs in vascular wall cells suggests their potential role in vascular disease. 8 -10 Some in vitro studies suggest potential atherogenic effects of PPAR␥ activation, 8,[13][14][15] whereas other studies associate PPAR␥ with potential vascular protective effects. 16 -21 Importantly, two independent in vivo studies using the LDL receptor knockout mouse demonstrated that PPAR␥ activators reduced development of hypercholesterolemia-induced atherosclerotic lesion formation.…”

Section: Conclusion-takenmentioning

confidence: 99%

See 1 more Smart Citation

Peroxisome Proliferator-Activated Receptor γ Ligands Increase Release of Nitric Oxide From Endothelial Cells

Calnek

Mazzella

Roser

et al. 2003

ATVB

276

158

View full text Add to dashboard Cite

Objective-Peroxisome proliferator-activated receptor ␥ (PPAR␥) ligands reduce lesion formation in animal models of atherosclerosis by mechanisms that have not been defined completely. We hypothesized that PPAR␥ ligands stimulate endothelial-derived nitric oxide release (·NO) to protect the vascular wall. Methods and Results-The PPAR␥ ligands, 15-deoxy-⌬ 12,14 -prostaglandin J 2 (15d-PGJ 2 ) or ciglitazone, stimulated a PPAR response element-luciferase reporter construct in transfected porcine pulmonary artery endothelial cells (PAECs), demonstrating that PPAR␥ was transcriptionally functional. Treatment with 15d-PGJ 2 or ciglitazone significantly increased release of ·NO from PAECs or human aortic endothelial cells and augmented calcium ionophore-induced ·NO release from human umbilical vein endothelial cells measured by chemiluminescence analysis of culture media. Increases in ·NO release caused by treatment with 15d-PGJ 2 occurred at 24 hours, but not after 1 to 16 hours, and were abrogated by treatment with the transcriptional inhibitor ␣-amanitin. Overexpression of PPAR␥ or treatment with 9-cis retinoic acid also enhanced PAEC ·NO release. Neither 15d-PGJ 2 nor ciglitazone altered eNOS mRNA, whereas 15d-PGJ 2 , but not ciglitazone, decreased eNOS protein. Key Words: peroxisome proliferator-activated receptor ␥ Ⅲ endothelium Ⅲ nitric oxide Ⅲ nitric oxide synthase Ⅲ thiazolidinedione T he production of nitric oxide (·NO) by vascular endothelial cells is critical for maintenance of normal vascular physiology. 1 In endothelial cells (ECs), the type III endothelial nitric oxide synthase (eNOS) produces ·NO from the amino acid L-arginine. Our preliminary observations, 2 as well as reports by others, [3][4][5] indicate that exogenous fatty acids alter EC ·NO production. The molecular mechanism contributing to fatty acid-induced alterations in EC ·NO production remain unexplored. One potential mechanism for fatty acidinduced alterations in gene expression is the activation of peroxisome proliferator-activated receptors (PPARs). Originally described in 1990, PPARs belong to the nuclear hormone receptor superfamily of ligand-activated transcription factors including steroid, thyroid, and retinoid hormone receptors. 6 Structurally diverse ligands including long-chain fatty acids, eicosanoids, thiazolidinediones, and fibrates activate PPARs, which form obligate heterodimers with the 9-cis retinoic acid receptor, RXR. 7 On ligand binding, PPARs become transcriptionally active at PPAR response elements (PPRE) and alter the expression of target genes. Conclusions-TakenPPAR␥ is expressed in vascular endothelial cells 8 -11 and smooth muscle cells. 12 The expression of PPARs in vascular wall cells suggests their potential role in vascular disease. 8 -10 Some in vitro studies suggest potential atherogenic effects of PPAR␥ activation, 8,[13][14][15] whereas other studies associate PPAR␥ with potential vascular protective effects. 16 -21 Importantly, two independent in vivo studies using the LDL receptor knockout mouse demo...

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Conclusion-takenmentioning

confidence: 99%

Peroxisome Proliferator-Activated Receptor γ Ligands Increase Release of Nitric Oxide From Endothelial Cells

Calnek

Mazzella

Roser

et al. 2003

ATVB

276

158

View full text Add to dashboard Cite

show abstract

“…10 PPAR␥ is expressed by human endothelial cells, including HUVECs. 5 Activation of this receptor can inhibit endothelial cell proliferation and may modulate PAI-1 expression, 5,11 reduce endothelin-1 production, 12 and induce apoptosis, 13 in particular in serum-free conditions. Activation of PPAR␥ results in inhibition of the AP-1 and NF-B pathways 3,12 that regulate the expression of adhesion molecules by activated endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

“…2 In atherosclerotic plaques, PPAR␥ is expressed by macrophage/foam cells, and activation of this receptor can inhibit macrophage activation. 3,4 Although PPAR␥ is also expressed by endothelial cells, 5 the possible effects of PPAR␥ activators in atherosclerotic plaques are currently unknown.…”

mentioning

confidence: 99%

Modulation of Vascular Inflammation In Vitro and In Vivo by Peroxisome Proliferator–Activated Receptor-γ Activators

et al. 2000

View full text Add to dashboard Cite

Background-Peroxisome proliferator-activated receptor-␥ (PPAR␥) is expressed in atherosclerotic plaques and in endothelial cells. The possible effects of PPAR␥ activators on endothelial activation and inflammatory response within the plaque are currently unknown. Methods and Results-We tested the hypothesis that PPAR␥ activators inhibit vascular cell adhesion molecule and intercellular adhesion molecule (ICAM-1) expression in cultured endothelial cells (evaluated by flow cytometry) and homing of monocyte/macrophages to atherosclerotic plaques in vivo. In endothelial cells, the PPAR␥ agonists troglitazone at 100 mol/L and 15-deoxy-⌬12,14 -prostaglandin J 2 (15d-PGJ2) at 20 mol/L markedly attenuated the tumor necrosis factor-induced expression of VCAM-1 and ICAM-1. A significant inhibition of VCAM-1 expression was also evident at 5 and 10 mol/L 15d-PGJ2 and 20 mol/L troglitazone. Expression of E-selectin and PECAM-1 was not altered. To confirm the biological relevance of these results, we assessed the effects of troglitazone on monocyte/macrophage homing to atherosclerotic plaques in apoE-deficient mice. A 7-day treatment with troglitazone (400 mg/kg) significantly reduced monocyte/macrophage homing to atherosclerotic plaques (236Ϯ77 versus 177Ϯ43 macrophages, Pϭ0.03); an even more striking inhibition was found at 3200 mg/kg troglitazone (344Ϯ76 versus 172Ϯ83 macrophages, Pϭ0.005). Conclusions-PPAR␥

show abstract

“…The identification of genetic markers for an increased risk of atherosclerosis is one possible approach to determine an individual risk profile. PPARg is present in all major cells of the vasculature: human endothelial cells (28), vascular smooth muscle cells (29), macrophages (2, 4, 5) and resident atherosclerotic lesion macrophages (30). Furthermore PPARs are implicated in differentiation, foam cell formation (5), apoptosis (7) and inflammation control (4, 15) of macrophages.…”

Section: Discussionmentioning

confidence: 99%

Lack of association between peroxisome proliferator-activated receptor-gamma-2 gene variants and the occurrence of coronary heart disease in patients with diabetes mellitus

Blüher

Klemm

Gerike³

et al. 2002

European Journal of Endocrinology

View full text Add to dashboard Cite

Objective: Recent evidence indicates that peroxisome proliferator-activated receptor-g (PPARg) is expressed at high levels in foam cells of atherosclerotic lesions, that PPARg agonists may directly modulate vessel wall function and that mutations in the PPARg-2 gene are associated with a reduced risk of coronary artery disease. Methods: We investigated whether known variants in the PPARg-2 gene are associated with the occurrence of coronary heart disease (CHD) in 365 patients with type 2 diabetes, prospectively characterised for the presence or absence of CHD. The Pro115Gln, Pro12Ala, Pro467Leu, Val290Met mutations and two polymorphisms C478T and C161T of the PPARg-2 gene were examined using PCR, denaturing gradient gel electrophoresis and direct sequencing. Results: The distribution of the Pro12Ala, Ala12Ala, C161T and T161T variants was not significantly different between patients with and without CHD, independent of the gender. The Pro12Ala ðP ¼ 0:011Þ and the Ala12Ala ðP ¼ 0:006Þ variant were associated with a higher body mass index (BMI) compared with the Pro12Pro genotype. A multiple logistic regression analysis introducing the typical risk factors for CHD (age, sex, hypertension, smoking, BMI .26 kg/m 2 , elevated low density lipoprotein cholesterol and haemoglobin A 1 c .7%) identified age .60, male gender, hypertension and a higher BMI, but not the PPARg-2 variants, as significant risk factors for CHD in our study groups. Conclusion: The PPARg-2 genotype was not associated with an increased or reduced risk of the occurrence of CHD and can therefore not be regarded as an independent risk factor for CHD in patients with diabetes mellitus.

show abstract

PPARγ Activation in Human Endothelial Cells Increases Plasminogen Activator Inhibitor Type-1 Expression

Cited by 345 publications

References 51 publications

Peroxisome Proliferator-Activated Receptor γ Ligands Increase Release of Nitric Oxide From Endothelial Cells

Peroxisome Proliferator-Activated Receptor γ Ligands Increase Release of Nitric Oxide From Endothelial Cells

Modulation of Vascular Inflammation In Vitro and In Vivo by Peroxisome Proliferator–Activated Receptor-γ Activators

Lack of association between peroxisome proliferator-activated receptor-gamma-2 gene variants and the occurrence of coronary heart disease in patients with diabetes mellitus

Contact Info

Product

Resources

About