Troglitazone has a reducing effect on thromboxane production

Hishinuma, Takanori; Yamazaki, Tohru; Mizugaki, Michinao

doi:10.1016/s0090-6980(00)00059-9

Cited by 18 publications

(8 citation statements)

References 22 publications

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“…Therefore, both synthesis and action of TX are suggested to be up-regulated in DM. We have shown previously that PPAR-␥ and its ligands also suppressed expression of the TX synthase gene (17), which is supported by the observation that TRO reduced TX production in human platelets and erythroleukemia cells (52). PPAR-␥ and its ligands may thus attenuate both synthesis and action of TX, exerting a beneficial effect on cardiovascular complications in DM patients.…”

Section: Inhibition Of Sp1 Activity By Ppar-␥-mentioning

confidence: 59%

Transcription Suppression of Thromboxane Receptor Gene by Peroxisome Proliferator-activated Receptor-γ via an Interaction with Sp1 in Vascular Smooth Muscle Cells

Sugawara

Uruno

Kudo

et al. 2002

Journal of Biological Chemistry

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Thromboxane (TX)A Thromboxane (TX)1 A 2 is a labile metabolite of arachidonic acid synthesized by TX synthase (1). TX is known to exert many biological effects such as platelet aggregation, contraction and growth of vascular smooth muscle cells (VSMCs) (2, 3), and renal electrolyte metabolism (4). TX is also known to play a pathophysiological role in the inflammatory diseases such as atherosclerosis (5) and glomerulonephritis (6). The biological action of TX is mediated via its specific membrane TX receptor (TXR). We previously isolated a cDNA for rat TXR (7), localized it in either the kidney (8) or testis (9), and identified its chromosomal localization (10). Moreover, we have isolated 5Ј-flanking region (FL) of the rat TXR gene and studied its transcription regulation in VSMCs (11).Peroxisome proliferator-activated receptor (PPAR)-␥ is a nuclear hormone receptor that was shown to transactivate adipocyte-specific genes and induce adipocyte differentiation (12). Either insulin-sensitizing thiazolidinediones including troglitazone (TRO) or 15-deoxy-⌬ 12,14 -prostaglandin J 2 (PGJ 2 ) (13, 14) has been identified as a ligand of PPAR-␥. Recently, PPAR-␥ has been shown to be present not only in adipocytes but also in vascular tissues including VSMCs (15), and an inhibitory effect of PPAR-␥ on gene expression in atherosclerosis has been studied. Activation of PPAR-␥ with its ligands suppressed expression of plasminogen activator inhibitor type 1 (16) in vascular endothelial cells and that of matrix metalloproteinase-9 in VSMCs (15). Moreover, we have observed that PPAR-␥ can suppress TX synthase gene transcription in macrophages (17).In the present study, we examined the role of PPAR-␥ in TXR gene expression in VSMCs. We observed that PPAR-␥ inhibited the TX-mediated cell growth of VSMCs and TXR mRNA expression. Suppression of TXR gene transcription was confirmed, and the suppression was shown to be dependent on a GC box-related sequence present at the Ϫ22/Ϫ7 region of TXR gene promoter (upstream of transcription start site), which was bound by Sp1 but not by PPAR-␥. PPAR-␥ was shown to interact physically with Sp1 by glutathione S-transferase (GST) pull-down assays. Taken together, PPAR-␥ was suggested to suppress TXR gene transcription via a protein-protein interaction with Sp1. An antiatherosclerotic action of PPAR-␥ by inhibiting TXR gene expression in VSMCs may be suggested. EXPERIMENTAL PROCEDURESPlasmids-Previously reported (11) and newly subcloned chimeric constructs containing rat TXR gene promoter and luciferase cDNA were used for transient transfection studies: Ϫ989/ϩ184-luc (989-bp 5Ј-flanking region (FL) and 184-bp 5Ј-untranslated region (UTR) of rat TXR gene); Ϫ809/ϩ184-luc (809-bp 5Ј-FL and 184-bp 5Ј-UTR); Ϫ489/ϩ184-luc (489-bp 5Ј-FL and 184-bp 5Ј-UTR); Ϫ213/ϩ184-luc (213-bp 5Ј-FL and 184-bp 5Ј-UTR); Ϫ78/ϩ184-luc (78-bp 5Ј-FL and 184-bp 5Ј-UTR); Ϫ78/ϩ120-luc (78-bp 5Ј-FL and 120-bp 5Ј-UTR); Ϫ47/ϩ120-luc (47-bp 5Ј-FL and 120-bp 5Ј-UTR); Ϫ39/ϩ120-luc (39-bp 5Ј-FL and 120-bp 5Ј-UTR); Ϫ22/ϩ120-luc (22-bp ...

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Section: Inhibition Of Sp1 Activity By Ppar-␥-mentioning

confidence: 59%

Transcription Suppression of Thromboxane Receptor Gene by Peroxisome Proliferator-activated Receptor-γ via an Interaction with Sp1 in Vascular Smooth Muscle Cells

Sugawara

Uruno

Kudo

et al. 2002

Journal of Biological Chemistry

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“…Our lab was the first to show that human platelets and megakaryocytes express functional PPARγ ( 55 ). The PPARγ ligands 15d-PGJ 2 and rosiglitazone potently inhibit thrombin-induced CD40L surface expression and thomboxane B 2 (TXB 2 ) production and dampen ADP-induced aggregation ( 56 ). Other studies have confirmed these findings and further demonstrated that rosiglitazone and 15d-PGJ 2 inhibited collagen-induced aggregation and prevented P-selectin exposure in vitro and in vivo ( 54 , 57 ).…”

Section: Pparγ Ligands Dampen Platelet Function From Healthy Donorsmentioning

confidence: 99%

Breaking the Mold: Transcription Factors in the Anucleate Platelet and Platelet-Derived Microparticles

et al. 2015

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Platelets are small anucleate blood cells derived from megakaryocytes. In addition to their pivotal roles in hemostasis, platelets are the smallest, yet most abundant, immune cells and regulate inflammation, immunity, and disease progression. Although platelets lack DNA, and thus no functional transcriptional activities, they are nonetheless rich sources of RNAs, possess an intact spliceosome, and are thus capable of synthesizing proteins. Previously, it was thought that platelet RNAs and translational machinery were remnants from the megakaryocyte. We now know that the initial description of platelets as “cellular fragments” is an antiquated notion, as mounting evidence suggests otherwise. Therefore, it is reasonable to hypothesize that platelet transcription factors are not vestigial remnants from megakaryocytes, but have important, if only partly understood functions. Proteins play multiple cellular roles to minimize energy expenditure for maximum cellular function; thus, the same can be expected for transcription factors. In fact, numerous transcription factors have non-genomic roles, both in platelets and in nucleated cells. Our lab and others have discovered the presence and non-genomic roles of transcription factors in platelets, such as the nuclear factor kappa β (NFκB) family of proteins and peroxisome proliferator-activated receptor gamma (PPARγ). In addition to numerous roles in regulating platelet activation, functional transcription factors can be transferred to vascular and immune cells through platelet microparticles. This method of transcellular delivery of key immune molecules may be a vital mechanism by which platelet transcription factors regulate inflammation and immunity. At the very least, platelets are an ideal model cell to dissect out the non-genomic roles of transcription factors in nucleated cells. There is abundant evidence to suggest that transcription factors in platelets play key roles in regulating inflammatory and hemostatic functions.

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“…Data from in vitro studies have shown that TZDs may have anti-platelet activity independent of their effects on hyperglycaemia [90,91]. Thrombin-induced platelet activation is dependent on phospholipase C and phosphatidylinositol 3-kinase activity, and TZDs have produced a reduction in the activities of both these enzymes in vitro [91].…”

Section: Platelet Activitymentioning

confidence: 99%

Thiazolidinediones as anti‐inflammatory and anti‐atherogenic agents

Ceriello

2007

Diabetes Metabolism Res

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In the last few years, there has been increasing focus on the impact of interventions on cardiovascular outcomes in patients with type 2 diabetes. Insulin resistance and hyperglycaemia often co-exist with a cluster of risk factors for coronary artery disease, but the underlying mechanisms leading to the development of such vascular complications are complex. The over-production of free radicals in patients suffering from diabetes results in a state of oxidative stress, which leads to endothelial dysfunction and a greater risk of atherosclerosis. Moreover, inflammatory factors which play a critical role in atherothrombosis and plaque rupture are often found to be at elevated levels in this patient population. Thiazolidinediones (TZDs) are now routinely used to manage glucose levels, and have been suggested to influence other cardiovascular risk factors and therefore the pathways leading to macrovascular events. Consequently, recent studies have investigated the anti-inflammatory and anti-atherogenic properties of TZDs. The data available up to the present time, in the context of the emerging cardiovascular outcome profiles of rosiglitazone and pioglitazone, will be discussed here.

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Troglitazone has a reducing effect on thromboxane production

Cited by 18 publications

References 22 publications

Transcription Suppression of Thromboxane Receptor Gene by Peroxisome Proliferator-activated Receptor-γ via an Interaction with Sp1 in Vascular Smooth Muscle Cells

Transcription Suppression of Thromboxane Receptor Gene by Peroxisome Proliferator-activated Receptor-γ via an Interaction with Sp1 in Vascular Smooth Muscle Cells

Breaking the Mold: Transcription Factors in the Anucleate Platelet and Platelet-Derived Microparticles

Thiazolidinediones as anti‐inflammatory and anti‐atherogenic agents

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