The vasoconstrictor effect of 8‐epi prostaglandin F<sub>2α</sub> in the hypoxic rat heart

Kromer, Brendan M.; Tippins, John R.

doi:10.1038/sj.bjp.0702433

Cited by 20 publications

(17 citation statements)

References 19 publications

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“…Activation of this feed-forward loop may underlie the augmented TP expression observed in CVD (6,7). In addition, oxidant-dependent mobilization of an intracellular TP reserve, via this novel mechanism, may explain the enhanced response to 8-iso-prostaglandin F 2a , another TP-dependent isoprostane (2), in oxidatively stressed isolated rat hearts (59). Conceptually, this feedforward loop is highly relevant to CVD where the milieu of vasoactive mediators generated includes TxA 2 , isoprostanes, and other NADPH oxidase activators.…”

Section: Discussionmentioning

confidence: 99%

Activation-dependent stabilization of the human thromboxane receptor: role of reactive oxygen species

Wilson

Cavanagh

Lesher

et al. 2009

Journal of Lipid Research

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Thromboxane A 2 (TxA 2 ), the principle product of platelet COX-1-dependent arachidonic acid metabolism, directs multiple pro-atherogenic processes via its receptor, TP. Oxidative challenge offsets TP degradation, a key component in limiting TxA 2 ʼs actions. Following TP activation, we observed cellular reactive oxygen species (ROS) generation coincident with increased TP expression. We examined the link between TP-evoked ROS and TP regulation. TP expression was augmented in TPa-transfected cells treated with a. This was reduced with a cellular antioxidant, N-acetyl cysteine, or two distinct NADPH oxidase inhibitors, diphenyleneiodonium and apocynin. Homologous upregulation of the native TP was also reduced in apocynintreated aortic smooth muscle cells (ASMCs) and was absent in ASMCs lacking an NADPH oxidase subunit (p47 2/2 ). TP transcription was not increased in IBOP-treated cells, indicating a posttranscriptional mechanism. IBOP induced translocation of TPa to the Golgi and reduced degradation of the immature form of the receptor. These data are consistent with a ROS-dependent mechanism whereby TP activation enhanced TP stability early in posttranscriptional biogenesis. Given the significant role played by TP and ROS in perturbed cardiovascular function, the convergence of TP on ROSgenerating pathways for regulation of TxA 2 -dependent events may be critical for cardiovascular disease.-Wilson,

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Section: Discussionmentioning

confidence: 99%

Activation-dependent stabilization of the human thromboxane receptor: role of reactive oxygen species

Wilson

Cavanagh

Lesher

et al. 2009

Journal of Lipid Research

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“…However, after an oxidative stress induced by 30 min of low flow and reperfusion or by a superoxide-generating system (i.e. xanthine and xanthine oxidase), 8-iso-prostaglandin F 2␣ became a potent vasoconstrictor, whereas the response to U46619 was unchanged (11). Responses to both agonists were inhibited by the TXA 2 R antagonist SQ29548, suggesting that they act upon the same receptor.…”

mentioning

confidence: 88%

The Mechanism of Oxidative Stress Stabilization of the Thromboxane Receptor in COS-7 Cells

Valentin

Field

Tippins

2004

Journal of Biological Chemistry

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The 8-iso-prostaglandin F 2␣ , a prostanoid produced in vivo by cyclooxygenase-independent free-radical-catalyzed lipid peroxidation, acts as a partial agonist on the thromboxane receptor (TXA 2 R) and is a potent vasoconstrictor in the oxidatively stressed isolated perfused rat heart. We hypothesized that the response in the isolated heart may be due to augmentation of TXA 2 R density, which may be initiated by the presence of oxidative radicals. Previous studies have shown that TXA 2 R density is increased during atherosclerosis on both the medial and intimal smooth muscle layers in human coronary arteries. Here we describe the effect of oxidative stress on TXA 2 R. The thromboxane A 2 receptor ␤ isoform (TXA 2 R␤) was transiently expressed in COS-7 cells. (TXA 2 ) 1 is an unstable arachidonate metabolite, implicated as a mediator in diseases such as myocardial infarction, stroke, and bronchial asthma (1). Binding of TXA 2 to its receptor, a polytopic membrane-spanning protein, induces vasoconstriction and platelet aggregation, as well as mitogenesis and hypertrophy of vascular smooth muscle cells (2). Two TXA 2 receptor (TXA 2 R) isoforms have been identified, TXA 2 R␣ (343 amino acids), which is mainly located in the placenta, and TXA 2 R␤ (407 amino acids), located in the endothelium; these isoforms are generated by the alternative splicing of a single gene (3, 4). The TXA 2 R is part of the G proteincoupled receptor superfamily, and evidence suggests that TXA 2 -induced production of second messenger inositol polyphosphates results from the activation of the G q11 family of heterotrimeric G proteins (5).Isoprostanes are formed by free radical attack on membrane phospholipids during oxidative stress (6). They are found in increased concentration in patients with coronary heart disease and are potent vasoconstrictors (7). We have shown that one of these, the 8-iso-prostaglandin F 2␣ , is a potent coronary vasoconstrictor, and its effect is exerted via partial agonist action on the TXA 2 R (8). This mechanism of action on TXA 2 R, in vascular smooth muscle and in platelets, has been confirmed in a TXA 2 R knock-out mouse (9). Our data suggested that a critical determinant of the intrinsic activity of the isoprostane is the TXA 2 R reserve, and this has subsequently been supported by another study (10). We have shown that, in the normal rat heart perfused at constant pressure in the Langendoff mode, 8-iso-prostaglandin F 2␣ had no effect, even though U46619, a TXA 2 R agonist, produced a pronounced vasoconstriction. However, after an oxidative stress induced by 30 min of low flow and reperfusion or by a superoxide-generating system (i.e. xanthine and xanthine oxidase), 8-iso-prostaglandin F 2␣ became a potent vasoconstrictor, whereas the response to U46619 was unchanged (11). Responses to both agonists were inhibited by the TXA 2 R antagonist SQ29548, suggesting that they act upon the same receptor.The rapidity of the change in response suggests that this is unlikely to be due to alterations in gene expressio...

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“…It was especially important that neither TxA 2 , assayed by its stable TxB 2 derivative nor 8-iso-PGF 2α , levels increased, since these eicosanoids possess strong vasoconstrictive properties (Kromer and Tippins, 1999;Yura et al, 1999). Only a small stimulation could be observed for PGF 2α .…”

Section: -5mentioning

confidence: 99%

Superoxide as a Messenger of Endothelial Function

Ullrich

Bachschmid²

2000

Biochemical and Biophysical Research Communications

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The vasoconstrictor effect of 8‐epi prostaglandin F_2α in the hypoxic rat heart

Cited by 20 publications

References 19 publications

Activation-dependent stabilization of the human thromboxane receptor: role of reactive oxygen species

Activation-dependent stabilization of the human thromboxane receptor: role of reactive oxygen species

The Mechanism of Oxidative Stress Stabilization of the Thromboxane Receptor in COS-7 Cells

Superoxide as a Messenger of Endothelial Function

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The vasoconstrictor effect of 8‐epi prostaglandin F2α in the hypoxic rat heart

Cited by 20 publications

References 19 publications

Activation-dependent stabilization of the human thromboxane receptor: role of reactive oxygen species

Activation-dependent stabilization of the human thromboxane receptor: role of reactive oxygen species

The Mechanism of Oxidative Stress Stabilization of the Thromboxane Receptor in COS-7 Cells

Superoxide as a Messenger of Endothelial Function

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Product

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The vasoconstrictor effect of 8‐epi prostaglandin F_2α in the hypoxic rat heart