PPARγ-Ligands Inhibit Migration Mediated by Multiple Chemoattractants in Vascular Smooth Muscle Cells

Goetze, Stephan; Xi, Xiao-Ping; Kawano, Hiroaki; Gotlibowski, Tina; Fleck, Eckart; Hsueh, Willa A.; Law, Ronald E.

doi:10.1097/00005344-199905000-00018

Cited by 182 publications

(121 citation statements)

References 52 publications

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“…This result suggests the mechanism of action of metformin is not due to an inhibition of intimal hyperplasia but rather to other mechanisms, such as modulation of endothelial function, lipid levels, plasminogen activator inhibitor-1 levels, or platelet reactivity. [5][6][7][8][9][10][11][12][13][14][15][16] We are unable to comment on the potential effects of thiazolidinediones on clinical outcomes compared with nonsensitizer therapy because this medication was not allowed due to potential drug interactions with tranilast. Analysis of our data, excluding insulin-dependent diabetics, showed preserved benefit with respect to MI and a continued trend toward benefit with respect to death (data not shown) in diabetic patients treated with metformin.…”

Section: Discussionmentioning

confidence: 99%

“…[1][2][3][4] Insulin sensitizers act by decreasing endogenous and exogenous insulin requirements and have other potentially beneficial effects on the cardiovascular system. [5][6][7][8][9][10][11][12][13][14][15][16] We hypothesized that diabetic patients enrolled in the Prevention of Restenosis with Tranilast and its Outcomes (PRESTO) Trial and treated with metformin would demonstrate a lower adverse event rate than diabetic patients treated with non-insulin-sensitizing medications.…”

mentioning

confidence: 99%

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Relation of metformin treatment to clinical events in diabetic patients undergoing percutaneous intervention

Kao

Tobis

McClelland

et al. 2004

The American Journal of Cardiology

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Relation of metformin treatment to clinical events in diabetic patients undergoing percutaneous intervention

Kao

Tobis

McClelland

et al. 2004

The American Journal of Cardiology

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“…7,11 In vascular smooth muscle cells and monocytes, activated PPAR␥ inhibits directed migration and targets the expression of matrix metalloproteinases downstream of the extracellular signal-regulated kinases 1 and 2 (ERK 1/2). 12,13 In addition, activated PPAR␥ has a number of other effects in the vasculature, including the modulation of adhesion molecule expression and the regulation of atherogenic and inflammatory processes (for review see Neve et al 14 ).…”

mentioning

confidence: 99%

Leptin Induces Endothelial Cell Migration Through Akt, Which Is Inhibited by PPARγ-Ligands

Goetze¹,

Bungenstock²,

Czupalla³

et al. 2002

Hypertension

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164

112

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Abstract-Migration of endothelial cells (EC) is a key event in angiogenesis that contributes to neovascularization in diabetic vasculopathy. Leptin induces angiogenesis and is elevated in obesity and hyperinsulinemia. The antidiabetic thiazolidinediones (TZD) inhibit leptin gene expression and vascular smooth muscle cell migration through activation of the peroxisome proliferator-activated receptor-␥ (PPAR␥). This study investigates the role of leptin in EC migration, the chemotactic signaling pathways involved, and the effects of the TZD-PPAR␥ ligands troglitazone (TRO) and ciglitazone (CIG) on EC migration. We demonstrate that leptin induces EC migration. Because activation of two signaling pathways, the phosphatidylinositol-3 kinase (PI3K)3 Akt3eNOS and the ERK1/2 MAPK pathway, is known to be involved in cell migration, we used the pharmacological inhibitors wortmannin and PD98059 to determine if chemotactic signaling by leptin involves Akt or ERK1/2, respectively. Both wortmannin and PD98059 significantly inhibited leptin-induced migration. Treatment with the TZD-PPAR␥-ligands TRO and CIG significantly inhibited the chemotactic response toward leptin. Both PPAR␥-ligands inhibited leptin-stimulated Akt and eNOS phosphorylation, but neither attenuated ERK 1/2 activation in response to leptin. The inhibition of Akt-phosphorylation was accompanied by a PPAR␥-ligand-mediated upregulation of PTEN, a phosphatase that functions as a negative regulator of PI3K3 Akt signaling. These experiments provide the first evidence that activation of Akt and ERK 1/2 are crucial events in leptin-mediated signal transduction leading to EC migration. Moreover, inhibition of leptin-directed migration by the PPAR␥-ligands TRO and CIG through inhibition of Akt underscores their potential in the prevention of diabetesassociated complications.

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“…Ang II is known to be a major proatherogenic factor by inducing inflammation in the vessel wall and stimulating proliferation and migration of VSMCs and monocytes. [113][114][115] Previous studies have shown that PPAR-␥ ligands modulate Ang II signaling both at the receptor level and downstream of the Ang II type-1 receptor (AT1-R). PPAR-␥ activators were found to downregulate AT1-R expression in VSMCs and block AT1-R-mediated extracellular signal regulated kinase 1/2 MAPK activation, which is crucial for VSMC proliferation and migration.…”

Section: Inflammation and Atherosclerosismentioning

confidence: 99%

Obesity, Peroxisome Proliferator-Activated Receptor, and Atherosclerosis in Type 2 Diabetes

Blaschke

Takata²,

Caglayan³

et al. 2006

ATVB

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138

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Abstract-Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear hormone receptor superfamily. The 3 PPAR isotypes, PPAR-␣, PPAR-␥, and PPAR-␦, play a key role in the regulation of lipid and glucose metabolism. Obesity and the interrelated disorders of the metabolic syndrome have become a major worldwide health problem. In this review, we summarize the critical role of PPARs in regulating inflammation, lipoprotein metabolism, and glucose homeostasis and their potential implications for the treatment of obesity, diabetes, and atherosclerosis. Key Words: PPARs Ⅲ atherosclerosis Ⅲ obesity Ⅲ diabetes T ype 2 diabetes is a complex metabolic disorder that affects between 6% and 20% of the population in Western industrialized societies. Around the globe, the prevalence of type 2 diabetes is expected to increase exponentially, especially among the young. 1 Type 2 diabetes is characterized by hyperglycemia, insulin resistance, and progressive loss of ␤-cell function throughout the course of the disease and is associated with dyslipidemia, hypertension, and obesity (components of the metabolic syndrome). 2 Both type 1 and type 2 diabetes are considered a coronary artery disease (CAD) risk equivalent. 3 However, CAD often precedes the onset of diabetes, because 50% of patients with new onset type 2 diabetes already have a CAD diagnosis.Components of the metabolic syndrome-insulin resistance, hypertension, low high-density lipoprotein (HDL), and hypertriglyceridemia-are themselves CAD risk factors, whereas hyperglycemia additionally contributes to vascular damage. Whether hyperinsulinemia and insulin resistance directly contribute to vascular damage is controversial and under active investigation. 4 Although type 1 and 2 diabetes are associated with increased atherosclerosis, the pathogenesis of CAD in diabetes is multifactorial. Changes in metabolic factors, increased oxidative stress and glycoxidation, endothelial dysfunction, inflammation, and the prothrombotic state, observed in diabetics play a role in cardiovascular complications of diabetes. 5 Initially, type 2 diabetes was referred to as disorder of carbohydrate metabolism. For the past decade, it was considered a disorder of fatty acid metabolism, because free fatty acids (FFAs) circulate in high levels in obesity and promote insulin resistance and hepatic glucose production. 6 Recently, increasing evidence indicates that abnormalities in adipokine secretion from fat and in mitochondrial metabolism play a central role in the pathogenesis of this disease. 7,8 Insulin resistance, defined as a defect in the ability of insulin to drive glucose into its major target tissue, skeletal muscle, 9 is a key factor in the pathogenesis of type 2 diabetes and a cofactor in the development of dyslipidemia, hypertension, and atherosclerosis. 10 Insulin resistance is present in Ͼ90% of people with type 2 diabetes and predates the development of hyperglycemia by many years. 11 In the early states, insulin resistance is ...

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PPARγ-Ligands Inhibit Migration Mediated by Multiple Chemoattractants in Vascular Smooth Muscle Cells

Cited by 182 publications

References 52 publications

Relation of metformin treatment to clinical events in diabetic patients undergoing percutaneous intervention

Relation of metformin treatment to clinical events in diabetic patients undergoing percutaneous intervention

Leptin Induces Endothelial Cell Migration Through Akt, Which Is Inhibited by PPARγ-Ligands

Obesity, Peroxisome Proliferator-Activated Receptor, and Atherosclerosis in Type 2 Diabetes

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