Thromboxane A2 receptor-mediated signal transduction in rabbit aortic smooth muscle cells

doi:10.1016/0306-3623(95)00025-9

General Pharmacology: The Vascular System

Volume 26, Issue 7, November 1995, Pages 1489-1498

General Pharmacology...

https://doi.org/10.1016/0306-3623(95)00025-9 Get rights and content

Abstract

1.
1. 9,11-Epithio-11,12-methenothromboxane A₂ (STA₂), a stable analogue of thromboxane A₂ (TXA₂), contracted rabbit aortic smooth muscles (RASM) and accumulated [³H]inositol phosphates in cultured RASM cells. The contraction and phosphoinositide hydrolysis were competitively inhibited by TXA₂ receptor antagonists, including ONO NT-126, S-145, SQ29548, KW3635, GR32191B and ONO3708.
2.
2. STA₂ inhibited [³H]ONO NT-126 binding in a concentration-dependent manner in membranes derived from cultured aortic smooth muscle cells, but GTPγS, a stable GTP analogue, did not affect STA₂-induced inhibition of [³H]ONO NT-126 binding.
3.
3. The time course analysis revealed that STA₂ rapidly decreased inositol phosphate level and thereafter increased. Pertussis toxin did not attenuate but rather increased STA₂-induced phosphoinositide hydrolysis.
4.
4. TXA₂ receptor stimulation results in at least two signaling pathways in RASM cells: stimulation and inhibition of phosphoinositide hydrolysis.

References (41)

P. Gresele et al.
BM13.177, a selective blocker of platelet and vessel wall thromboxane receptors, is active in man
Lancet
(1984)
K. Hirata et al.
Involvement of rho p21 in the GTP-enhanced calcium ion sensitivity of smooth muscle contraction
J. Biol. Chem.
(1992)
Y. Kawahara et al.
Elevation of cytoplasmic free calcium concentration by stable thromboxane A₂ analogue in human platelets
Biochem. Biophys. Res. Commun.
(1983)
I. Litosch et al.
G protein-mediated inhibition of phospholipase C activity in a solubilized membrane preparation
J. Biol. Chem.
(1993)
O.H. Lowry et al.
Protein measurement with the folin phenol reagent
J. Biol. Chem.
(1951)
I. Matsuoka et al.
Possible mechanism of α₂-adrenoceptor-mediated potentiation of thromboxane A₂-induced phospholipase C activation in rabbit platelets
Eur. J. Pharmacol.
(1990)
N. Nakahata et al.
The presence of thromboxane A₂ receptors in cultured astrocytes from rabbit brain
Brain Res.
(1992)
N. Nakahata et al.
Thromboxane A₂ activates phospholipase C in astrocytoma cells via pertussis toxin-insensitive G-protein
Eur. J. Pharmacol.
(1989)
S. Nigam et al.
Thromboxane A₂ analogue U46619 enhances tumour cell proliferation in HeLa cells via specific receptors which are apparently distinct from TXA₂ receptors on human platelets
FEBS. Lett.
(1993)
H. Ninomiya et al.
Epithio-11,12-methanothromboxane A₂ stimulates inositol phosphates accumulation in isolated canine mesenteric artery strips
J. J. Pharmac.
(1991)

R.M. Nusing et al.

Characterization and chromosomal mapping of the human thromboxane A₂ receptor gene

J. Biol. Chem.

(1993)

M.K. Raychowdhury et al.

Alternative splicing produces a divergent cytoplasmic tail in the human endothelial thromboxane A₂ receptor

J. Biol. Chem.

(1994)

G.T.G. Swayne et al.

Evidence for homogeneity of thromboxane A₂ receptor using structurally different antagonists

Eur. J. Pharmacol.

(1988)

K. Takahara et al.

The response to thromboxane A₂ analogues in human platelets

F. Ushikubi et al.

Purification of the thromboxane A₂/prostaglandin H₂ receptor from human platelets

J. Biol. Chem.

(1989)

J.J. Baldassare et al.

Reconstitution of thromboxane A₂ receptor-stimulated phosphoinositide hydrolysis in isolated platelet membranes: involvement of phosphoinositide-specific phospholipase C-β and GTP-binding protein Gq

Biochem. J.

(1993)

M.J. Berridge

Inositol trisphosphate and diacylglycerol as second messengers

Biochem. J.

(1984)

L.F. Brass et al.

Inositol 1,4,5-trisphosphate-induced granule secretion in platelets

G.W. Dorn

Tissue- and species-specific differences in ligand binding to thromboxane A₂ receptors

Am. J. Physiol.

(1991)

G.W. Dorn et al.

Increased platelet thromboxane A₂-prostaglandin H₂ receptors in patients with acute myocardial infarction

Circulation

(1990)

Cited by (19)

Caffeic acid phenethyl ester analogues as selective inhibitors of 12-lipoxygenase product biosynthesis in human platelets
2023, International Immunopharmacology
The inflammatory response is an essential process for the host defence against pathogens. Lipid mediators are important in coordinating the pro-inflammatory and pro-resolution phases of the inflammatory process. However, unregulated production of these mediators has been associated with chronic inflammatory diseases such as arthritis, asthma, cardiovascular diseases, and several types of cancer. Therefore, it is not surprising that enzymes implicated in the production of these lipid mediators have been targeted for potential therapeutic approaches. Amongst these inflammatory molecules, the 12-hydroxyeicosatetraenoic acid (12(S)-HETE) is abundantly produced in several diseases and is primarily biosynthesized via the platelet’s 12-lipoxygenase (12-LO) pathway. To this day, very few compounds selectively inhibit the 12-LO pathway, and most importantly, none are currently used in the clinical settings. In this study, we investigated a series of polyphenol analogues of natural polyphenols that inhibit the 12-LO pathway in human platelets without affecting other normal functions of the cell. Using an ex vivo approach, we found one compound that selectively inhibited the 12-LO pathway, with IC₅₀ values as low as 0.11 µM, with minimal inhibition of other lipoxygenase or cyclooxygenase pathways. More importantly, our data show that none of the compounds tested induced significant off-target effects on either the platelet’s activation or its viability. In the continuous search for specific and better inhibitors targeting the regulation of inflammation, we characterized two novel inhibitors of the 12-LO pathway that could be promising for subsequent in vivo studies.
The association between thromboxane A<inf>2</inf> receptor gene polymorphisms and the risk of cerebral infarction
2020, Clinical Neurology and Neurosurgery
Citation Excerpt :
TXA2 can be generated from prostaglandin H2 by thromboxane-A synthase in activated platelets, but aspirin can restrain platelet cyclooxygenase 1 then inhibit the formation of prostaglandin H2, and finally reduce the production of TXA2 [18]. TXA2 has prothrombotic properties: TXA2 can in turn accelerate platelets aggregation and new platelets activation [7]. Platelets aggregation is attained by the up-regulating expression of the glycoprotein complex GPIIb/IIIa on the cell membrane of platelets, and the aggregation can be blocked by clopidogrel [19].
To explore the association between thromboxane A₂ receptor (TXA₂R) gene polymorphisms and the risk of cerebral infarction. We screened the relevant publications through the search engines in PubMed, Google Scholar, Embase, Web of Science, and China National Knowledge Infrastructure (the latest search update was performed on July 1, 2020). Gene-disease associations were measured using the estimation of OR (95 % CI) based on five genetic inheritance models. Totally three studies were included in this meta-analysis. TXA₂R rs768963 polymorphism in homozygote comparison (OR = 1.86, 95 % CI: 1.35–2.56), heterozygote comparison (OR = 1.81, 95 % CI: 1.37–2.39), and dominant model (OR = 1.82, 95 % CI: 1.39–2.37) emerged as risk factors for cerebral infarction. Besides, an increased cerebral infarction risk was observed in the heterozygote comparison (OR = 1.39, 95 % CI: 1.03–1.88) for TXA₂R rs2271875 polymorphism. None of the five models showed any association between TXA₂R rs4523 polymorphism and cerebral infarction risk. In conclusion, this is the first meta-analysis verifying that TXA₂R rs768963 polymorphism and TXA₂R rs2271875 polymorphism may be associated with the risk of cerebral infarction.
Resistance training-induced decreases in central arterial compliance is associated with increases in serum thromboxane B<inf>2</inf> concentrations in young men
2018, Artery Research
Citation Excerpt :
In contrast, the functional elements are regulated by some vasoconstrictive mediators.11,12 In particular, among vasoconstrictive mediators, thromboxane (TX) is produced from the platelets and has potent vasoconstrictory and platelet aggregation effects.13–15 The TX receptor exists on vascular smooth muscle cell.16
Reduction in central arterial compliance is an independent risk factor for cardiovascular disease, and is caused by high-intensity resistance training. The thromboxane has both potent vasoconstrictive and platelet aggregation effects, and is associated with cardiovascular diseases. However, whether thromboxane is involved in resistance training-induced decrease in central arterial compliance is unclear. The present study aimed to investigate relationships between circulating thromboxane levels and central arterial compliance in both cross-sectional and longitudinal (i.e., resistance training) designs.
First, in a cross-sectional study, we assessed association between circulating thromboxane concentrations and central arterial compliance in 63 young men, who showed significant negative correlation between those parameters. Second, in a longitudinal study, we examined effects of high-intensity resistance training on circulating thromboxane concentrations and central arterial compliance and relationship among changes from baseline in those parameters. Young sedentary men were assigned to control (n = 7) or training (n = 17) groups. Subjects in training group underwent four-week supervised high-intensity resistance training. Resistance training significantly elevated circulating thromboxane concentrations and decreased central arterial compliance; no significant change was observed in control group, and there was significant correlation between changes in those parameters.
circulating thromboxane is possible mechanism explaining resistance training-induced decrease in central arterial compliance in young men.
The role of platelets in the pathophysiology of atherosclerosis and its complications
2018, Cardiovascular Thrombus: From Pathology and Clinical Presentations to Imaging, Pharmacotherapy and Interventions
Atherosclerosis, the principal cause of coronary heart disease and stroke, is characterized by the development of plaques, within the major arteries, which consist of a necrotic fat-rich core and an overlying fibrous cap. Inflammation is a key pathophysiological feature of atherosclerosis, and contributes both to the progression of plaques and to their rupture. Although classically leukocytes have been the main mediators of inflammation, it is now recognized that platelets also play a key role, and may modulate inflammation through their interactions with leukocytes. In the context of atherosclerosis, therefore, platelets may contribute not only to occlusive thrombus formation but also to the development of the plaque itself. In this chapter, we will review the role of platelets in the pathophysiology of atherosclerosis and discuss the potential therapeutic implications of this.
P-selectin inhibition reduces severity of acute experimental pancreatitis
2009, Pancreatology
Background: Acute pancreatitis (AP) is characterized by disturbed pancreatic microcirculation with tissue necrosis. Platelet and leukocyte activation contributes to microcirculatory disorders and inflammatory tissue infiltration. P-selectin mediates the adhesion of both activated platelets and leukocytes to the vessel wall. The aim of this study was to investigate the effect of P-selectin inhibition by monoclonal antibodies (AB) on experimental AP. Methods: AP was induced in rats by glycodeoxycholic acid (GDOC) intraductally and by cerulein infusion. Animals were divided into4 groups: (1) severe AP (GDOC); (2) severe AP + platelet inhibition (GDOC + selectin AB); (3) control (Ringer); (4) control + platelet inhibition (Ringer + selectin AB). 24 h after AP induction, histologyand serum (amylase,thromboxaneA2) were evaluated (6 animals per group). In additional 12 animals of each group, platelet and leukocyte activation as well as erythrocyte flow patterns were evaluated by intravital microscopy 12 h after AP induction. Results: AP induction caused significant tissue inflammation and necrosis with increased amylase and thromboxane levels. Prophylactic inhibition of P-selectin reduced tissue inflammation and necrosis significantly. Severe AP led to significantly more adherent platelets and leukocytes in capillaries and venules. In contrast, antibody-treated animals showed significantly reduced plate-let-endothelium interaction compared with untreated AP animals. Antibody application in control animals without AP did not induce any changes compared with healthy control animals. Conclusion: Inhibition of P-selectin reduces tissue damage in experimental AP. This is associated with a reduction in platelet-and leukocyte-endothelium interaction and an improvement in pancreatic microcirculation.
Thromboxane A<inf>2</inf>: Physiology/pathophysiology, cellular signal transduction and pharmacology
2008, Pharmacology and Therapeutics
Thromboxane A₂ (TXA₂), an unstable arachidonic acid metabolite, elicits diverse physiological/pathophysiological actions, including platelet aggregation and smooth muscle contraction. TXA₂ has been shown to be involved in allergies, modulation of acquired immunity, atherogenesis, neovascularization, and metastasis of cancer cells. The TXA₂ receptor (TP) communicates mainly with G_q and G₁₃, resulting in phospholipase C activation and RhoGEF activation, respectively. In addition, TP couples with G₁₁, G₁₂, G₁₃, G₁₄, G₁₅, G₁₆, G_i, G_s and G_h. TP is widely distributed in the body, and is expressed at high levels in thymus and spleen. The second extracellular loop of TP is an important ligand-binding site, and Asp¹⁹³ is a key amino acid. There are two alternatively spliced isoforms of TP, TPα and TPβ, which differ only in their C-terminals. TPα and TPβ communicate with different G proteins, and undergo hetero-dimerization, resulting in changes in intracellular traffic and receptor protein conformations. TP cross-talks with receptor tyrosine kinases, such as EGF receptor, to induce cell proliferation and differentiation. TP is glycosylated in the N-terminal region for recruitment to plasma membranes. Furthermore, TP conformation is changed by coupling to G proteins, showing several states of agonist binding. Finally, several drugs modify TP-mediated events; these include cyclooxygenase inhibitors, TXA₂ synthase inhibitors and TP antagonists. Some flavonoids of natural origin also have TP receptor antagonistic activity. Recent advances in TP research have clarified TXA₂-mediated events in detail, and further study will supply more beneficial information about TXA₂ pathophysiology.

View all citing articles on Scopus

View full text

General paperThromboxane A2 receptor-mediated signal transduction in rabbit aortic smooth muscle cells

Abstract

Lancet

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

J. Biol. Chem.

Eur. J. Pharmacol.

Brain Res.

Eur. J. Pharmacol.

FEBS. Lett.

J. J. Pharmac.

J. Biol. Chem.

J. Biol. Chem.

Eur. J. Pharmacol.

J. Biol. Chem.

Reconstitution of thromboxane A2 receptor-stimulated phosphoinositide hydrolysis in isolated platelet membranes: involvement of phosphoinositide-specific phospholipase C-β and GTP-binding protein Gq

Biochem. J.

Inositol trisphosphate and diacylglycerol as second messengers

Biochem. J.

Inositol 1,4,5-trisphosphate-induced granule secretion in platelets

Tissue- and species-specific differences in ligand binding to thromboxane A2 receptors

Am. J. Physiol.

Increased platelet thromboxane A2-prostaglandin H2 receptors in patients with acute myocardial infarction

Circulation

General paper
Thromboxane A₂ receptor-mediated signal transduction in rabbit aortic smooth muscle cells

Reconstitution of thromboxane A₂ receptor-stimulated phosphoinositide hydrolysis in isolated platelet membranes: involvement of phosphoinositide-specific phospholipase C-β and GTP-binding protein Gq

Tissue- and species-specific differences in ligand binding to thromboxane A₂ receptors

Increased platelet thromboxane A₂-prostaglandin H₂ receptors in patients with acute myocardial infarction