Insulin resistance and cardiovascular disease: the role of PPARγ                 activators beyond their anti-diabetic action

Walcher, Daniel

doi:10.3132/dvdr.2004.011

Cited by 20 publications

(16 citation statements)

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“…34 However, although PPAR-␥ agonists have been shown previously to restore proangiogenic factors, upregulate HO-1, 10 and increase the production of VEGF in vitro [35][36][37] and in vivo, 18 rosiglitazone failed to alter angiogenic factors in the RUPP rat in the present study. A recent study, involving the induction of HO-1 in RUPP rats via the administration of cobalt (III) protoporphyrin IX chloride, demonstrated that, as a result of cobalt (III) protoporphyrin IX chloride treatment, placental expression of HO-1 was increased, and there was a significant shift in the angiostatic balance ratio (sFlt-1:VEGF).…”

Section: Discussioncontrasting

confidence: 43%

“…In models of diabetes mellitus and cardiovascular disease, activation of PPAR-␥ has been shown to restore vascular structure and correct endothelial dysfunction, [17][18][19] resulting in a reduction in the elevated blood pressure associated with hypertensive conditions. 20 -22 In the present study, administration of the PPAR-␥ agonist rosiglitazone to RUPP rats ameliorated both hypertension and endothelial dysfunction via a HO-1-dependent pathway.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussioncontrasting

confidence: 43%

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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“…Furthers, PPARγ activation leads to the following responses within the vasculature: (a) in ECs, it inhibits endothelial inflammation by suppressing inflammatory gene expression, (b) in VSMCs, it inhibits proliferation and migration, and promotes apoptosis, and (c) in macrophages, it suppresses inflammation by regulating gene expression and increases cholesterol uptake and efflux. The literature on these beneficial effects of PPARγ activation has been extensively reviewed elsewhere (Bishop-Bailey, 2000;Duan et al, 2008;Li and Palinski, 2006;Marx et al, 2004;Schiffrin, 2005;Touyz and Schiffrin, 2006;Walcher and Marx, 2004).…”

Section: Pparγ In Vascular Cellsmentioning

confidence: 99%

“…Several lines of evidence suggest that endothelial dysfunction plays a key role in the development of both macro-and microangiopathy in patients with inflammatory-associated diseases as atherosclerosis, hypercholesterolemia, hypertension, stroke, and diabetes, as well as in animal models of these diseases (Cai and Harrison, 2000;Kobayashi et al, 2000, Landmesser et al, 2004Matsumoto et al, 2003Matsumoto et al, , 2004bMatsumoto et al, , 2005Triggle et al, 2003). Although the genesis of this endothelial dysfunction and its associated vasomotor abnormalities remains poorly understood, there have been recent demonstrations that in cardiovascular diseases, activation of PPARγ not only has cardio-protective effects, but also restores vascular structure and corrects endothelial dysfunction (Bishop-Bailey, 2000;Li and Palinski, 2006;Schiffrin, 2005;Touyz and Schiffrin, 2006;Walcher and Marx, 2004). Because of these beneficial effects, a given activator of PPARγ may have a therapeutic potential for the prevention of cardiovascular diseases that lies beyond its actions on carbohydrate and lipid metabolism.…”

Section: Introductionmentioning

confidence: 99%

“…Substantial evidence has accrued to indicate that PPARγ are expressed in all the major cells found in vascular beds, and that this receptor is activated not only by natural ligands such as free fatty acids and eicosanoids, but also by the insulin-sensitizing, thiazolidinedione (TZD) class of agents (including troglitazone, ciglitazone, rosiglitazone, and pioglitazone) (BishopBailey, 2000;Blaschke et al, 2006a;Li and Palinski, 2006;Schiffrin, 2005;Touyz and Schiffrin, 2006;Walcher and Marx, 2004). The TZDs are currently used in the treatment of diabetic hyperglycemia (Stumvoll and Haring, 2002), although these compounds may have direct beneficial effects on cardiovascular risk that are independent of their hypoglycemic actions (Martens et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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Relationships among ET-1, PPAR.GAMMA., oxidative stress and endothelial dysfunction in diabetic animals

Matsumoto

Kobayashi

Kamata

2008

J. Smooth Muscle Res.

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Macro-and microvascular disorders currently represent the principal causes of morbidity and mortality in patients with diseases involving the cardiovascular system, such as atherosclerosis, hypertension, stroke, and diabetes. Abnormal vasomotor responses and impaired endothelium-dependent vasodilation have been demonstrated in a number of vessels in a variety of animal models and in humans with such diseases. Endothelial dysfunction plays a key role in the development of these diseases, yet the genesis of this endothelial dysfunction and its associated vasomotor abnormalities remain poorly understood. Peroxisome proliferator-activated receptor (PPAR)γ is a nuclear receptor and transcription factor in the steroid superfamily, and PPARγ agonists (the thiazolidinediones) are used clinically to treat type 2 diabetes. Recent studies have revealed that as well as being involved in adipogenesis and in increased sensitivity to insulin, PPARγ plays critical roles in the vasculature. In the present review, we discuss the beneficial effects of PPARγ agonists on vasomotor activities, focusing in particular on endothelium-dependent relaxation in vessels affected by cardiovascular diseases.

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Pharmakotherapie des Diabetes mellitus Typ 2

Jacob

Marx²

2006

Internist

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Patients with diabetes type 2 are not directly endangered by dysglycemia but they suffer vascular complications. The diabetic patient with existing cardiovascular disease has a particularly high risk for further cardiovascular complications and therefore requires specific attention. This is not only due to the hyperglycemia, but due to the coexistence of further cardiovascular risk factors, such as hypertension, dyslidemia, visceral fat accumulation, chronic inflammation and coagulopathy, also clinically described as the metabolic syndrome. These patients need an intense and multi-modal therapeutic approach, not only for improvement of glycemic control. Also other vascular risk factors should be handled aggressively, such as blood pressure, coagulopathy and dyslipidemia. Recent studies--as STENO 2--indicate that a multi-modal and aggressive approach in diabetic patients can markedly improve their prognosis. Therefore, the current practice of a glucocentric approach should be changed towards a more vascular approach.

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Insulin resistance and cardiovascular disease: the role of PPARγ activators beyond their anti-diabetic action

Cited by 20 publications

References 84 publications

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

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

Relationships among ET-1, PPAR.GAMMA., oxidative stress and endothelial dysfunction in diabetic animals

Pharmakotherapie des Diabetes mellitus Typ 2

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