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Journal of the American College of... Jul 2022
Topics: Aspirin; Blood Platelets; Humans; Thromboxane B2; Thromboxanes
PubMed: 35835497
DOI: 10.1016/j.jacc.2022.04.053 -
Arteriosclerosis, Thrombosis, and... Apr 2022TP (thromboxane A receptor) plays an eminent role in the pathophysiology of endothelial dysfunction and cardiovascular disease. Moreover, its expression is reported to...
BACKGROUND
TP (thromboxane A receptor) plays an eminent role in the pathophysiology of endothelial dysfunction and cardiovascular disease. Moreover, its expression is reported to increase in the intimal layer of blood vessels of cardiovascular high-risk individuals. Yet it is unknown, whether TP upregulation per se has the potential to affect the homeostasis of the vascular endothelium.
METHODS
We combined global transcriptome analysis, lipid mediator profiling, functional cell analyses, and in vivo angiogenesis assays to study the effects of endothelial TP overexpression or knockdown/knockout on the angiogenic capacity of endothelial cells in vitro and in vivo.
RESULTS
Here we report that endothelial TP expression induces COX-2 (cyclooxygenase-2) in a G- and G-dependent manner, thereby promoting its own activation via the auto/paracrine release of TP agonists, such as PGH (prostaglandin H) or prostaglandin F but not TxA (thromboxane A). TP overexpression induces endothelial cell tension and aberrant cell morphology, affects focal adhesion dynamics, and inhibits the angiogenic capacity of human endothelial cells in vitro and in vivo, whereas TP knockdown or endothelial-specific TP knockout exerts opposing effects. Consequently, this TP-dependent feedback loop is disrupted by pharmacological TP or COX-2 inhibition and by genetic reconstitution of PGH-metabolizing prostacyclin synthase even in the absence of functional prostacyclin receptor expression.
CONCLUSIONS
Our work uncovers a TP-driven COX-2-dependent feedback loop and important effector mechanisms that directly link TP upregulation to angiostatic TP signaling in endothelial cells. By these previously unrecognized mechanisms, pathological endothelial upregulation of the TP could directly foster endothelial dysfunction, microvascular rarefaction, and systemic hypertension even in the absence of exogenous sources of TP agonists.
Topics: Cyclooxygenase 2; Endothelial Cells; Feedback; Homeostasis; Humans; Receptors, Thromboxane; Receptors, Thromboxane A2, Prostaglandin H2; Thromboxane A2; Thromboxanes
PubMed: 35236104
DOI: 10.1161/ATVBAHA.121.317380 -
Medicinal Research Reviews Sep 1991
Review
Topics: Animals; Humans; Prostaglandin Endoperoxides, Synthetic; Prostaglandins D; Prostaglandins H; Prostaglandins, Synthetic; Receptors, Prostaglandin; Receptors, Thromboxane; Sulfonamides; Thromboxane A2; Thromboxanes
PubMed: 1834898
DOI: 10.1002/med.2610110504 -
American Journal of Obstetrics and... Jun 1985The gynecologic and obstetric implications of the smooth muscle-relaxing, antiaggregatory prostacyclin and its endogenous antagonist, thromboxane A2, are reviewed. In... (Review)
Review
The gynecologic and obstetric implications of the smooth muscle-relaxing, antiaggregatory prostacyclin and its endogenous antagonist, thromboxane A2, are reviewed. In addition to the vascular wall and circulating platelets, which are primary sources for prostacyclin and thromboxane A2, respectively, reproductive tissues produce great amounts of these prostanoids, evidently for the regulation of the vascular tone and/or vascular platelet interaction. Several gynecologic and obstetric disorders are characterized by abnormalities in prostacyclin and/or thromboxane A2. In primary menorrhagia the uterine release of prostacyclin is increased, and consequently menstrual blood loss can be reduced with various prostaglandin synthesis inhibitors. Prostacyclin relaxes the nonpregnant myometrium in vitro and may also do so in vivo, although intravenous infusion of prostacyclin has no effect upon the uterine contractility in nonpregnant or pregnant subjects. Patients with pelvic endometriosis may have increased levels of prostacyclin and thromboxane A2 metabolites in the peritoneal fluid. The prostacyclin/thromboxane A2 balance shifts to thromboxane A2 dominance in patients with gynecologic cancer. During pregnancy the production of prostacyclin and thromboxane A2 increases in the mother and fetoplacental tissue. Preeclampsia and other chronic placental insufficiency syndromes are accompanied by prostacyclin deficiency in the mother and in fetomaternal tissues and by an overproduction of thromboxane A2, at least in the placenta. These changes may account for the vasoconstriction and platelet hyperactivity, which are pathognomonic for hypertensive pregnancies. By directing the prostacyclin/thromboxane A2 balance to prostacyclin dominance (by dietary manipulation, administration of prostacyclin and/or its analogues, drugs with prostacyclin-stimulating and/or thromboxane A2-inhibiting action), it may be possible to prevent and/or treat hypertensive pregnancy complications in the future.
Topics: 6-Ketoprostaglandin F1 alpha; Animals; Ascitic Fluid; Endometriosis; Epoprostenol; Estrogens; Female; Genital Diseases, Female; Genital Neoplasms, Female; Humans; Hypertension; Menorrhagia; Platelet Aggregation; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnancy Complications, Cardiovascular; Progestins; Thromboxane A2; Thromboxane B2; Thromboxanes; Uterine Contraction; Vasoconstriction
PubMed: 3890549
DOI: 10.1016/s0002-9378(85)80221-0 -
Prostaglandins and Medicine Jun 1980It has been thought that blood vessels apart from the umbilical artery produce little or no thromboxane (TX) A2. However selective inhibitors of TXA2 biosynthesis have... (Review)
Review
It has been thought that blood vessels apart from the umbilical artery produce little or no thromboxane (TX) A2. However selective inhibitors of TXA2 biosynthesis have substantial effects on vessel physiology, suggesting that small amounts of TXA2 may be important in regulating function. This indirect evidence is now supported by direct measurements of TXB2 (the produce of TXA2 conversion) using both gas chromatography-mass spectrometry (GCMS) and radioimmunoassays. At least four independent laboratories have now demonstrated TXB2 production by various blood vessels. These studies suggest that vessel wall TXA2 is present in amounts more than adequate to exert biological actions on both vascular reactivity and on platelets. This may require re-evaluation and revision of present concepts of hypertension and thrombosis.
Topics: Animals; Blood Vessels; Humans; Hypertension; Thrombosis; Thromboxane A2; Thromboxanes
PubMed: 6997907
DOI: 10.1016/0161-4630(80)90051-8 -
Archives of Surgery (Chicago, Ill. :... Aug 2005Hepatic injury after hepatic stress is caused by several mechanisms, including inflammatory reaction and microcirculatory disturbance. Levels of thromboxane, a... (Review)
Review
Hepatic injury after hepatic stress is caused by several mechanisms, including inflammatory reaction and microcirculatory disturbance. Levels of thromboxane, a vasoconstrictive eicosanoid, have been shown to increase in systemic circulation after different types of hepatic stress such as endotoxemia, hepatic ischemia-reperfusion, hepatectomy, liver transplantation, hemorrhagic shock and resuscitation, hepatic cirrhosis, and alcoholic liver injury. The production of thromboxane from the liver is also enhanced under these stresses, which may act on the liver in an autocrine or a paracrine fashion. Kupffer cells, resident hepatic macrophages, may be a major source of stress-induced thromboxane, although other cell types in the liver such as sinusoidal endothelial cells and hepatocytes may also produce this eicosanoid. Thromboxane induces hepatic damage through vasoconstriction, platelet aggregation, induction of leukocyte adhesion, up-regulation of proinflammatory cytokines, and induction of other vasoconstrictor release. In this regard, administration of cyclooxygenase inhibitor, specific thromboxane synthase inhibitor, and specific thromboxane receptor antagonists has been shown to protect from severe hepatic injury elicited by these hepatic stresses. Furthermore, blockade of Kupffer cell function by administration of gadolinium chloride showed salutary effects in preventing hepatic damage in bile duct ligation models. This review article summarizes the recent knowledge of the role of thromboxane in various types of hepatic stress and the effects of thromboxane inhibitors in these models.
Topics: Animals; Biomarkers; Disease Progression; Female; Humans; Kupffer Cells; Liver; Liver Circulation; Liver Diseases; Male; Prognosis; Receptors, Thromboxane; Risk Assessment; Sensitivity and Specificity; Severity of Illness Index; Thromboxanes
PubMed: 16103291
DOI: 10.1001/archsurg.140.8.801 -
Agents and Actions. Supplements 1992Enhanced platelet biosynthesis of thromboxane A2 is associated with several cardiovascular risk factors, as a consequence of a direct effect on platelet biochemistry... (Review)
Review
Enhanced platelet biosynthesis of thromboxane A2 is associated with several cardiovascular risk factors, as a consequence of a direct effect on platelet biochemistry and/or some form of endothelial dysfunction. Moreover, episodic increases in thromboxane biosynthesis occur in acute coronary and cerebral ischemic syndromes. Thromboxane-dependent platelet activation represents an important mechanism that amplifies the consequences of acute vascular lesions as well as those of long-standing metabolic or hemodynamic disturbances, and results in increased risk of vascular occlusive events.
Topics: Animals; Cardiovascular Diseases; Humans; Risk Factors; Thromboxanes
PubMed: 1632286
DOI: 10.1007/978-3-0348-7262-1_2 -
Journal of the American College of... Jul 2022Persistent systemic thromboxane generation, predominantly from nonplatelet sources, in aspirin (ASA) users with cardiovascular disease (CVD) is a mortality risk factor.
BACKGROUND
Persistent systemic thromboxane generation, predominantly from nonplatelet sources, in aspirin (ASA) users with cardiovascular disease (CVD) is a mortality risk factor.
OBJECTIVES
This study sought to determine the mortality risk associated with systemic thromboxane generation in an unselected population irrespective of ASA use.
METHODS
Stable thromboxane B metabolites (TXB-M) were measured by enzyme-linked immunosorbent assay in banked urine from 3,044 participants (mean age 66 ± 9 years, 53.8% women) in the Framingham Heart Study. The association of TXB-M to survival over a median observation period of 11.9 years (IQR: 10.6-12.7 years) was determined by multivariable modeling.
RESULTS
In 1,363 (44.8%) participants taking ASA at the index examination, median TXB-M were lower than in ASA nonusers (1,147 pg/mg creatinine vs 4,179 pg/mg creatinine; P < 0.0001). TXB-M were significantly associated with all-cause and cardiovascular mortality irrespective of ASA use (HR: 1.96 and 2.41, respectively; P < 0.0001 for both) for TXB-M in the highest quartile based on ASA use compared with lower quartiles, and remained significant after adjustment for mortality risk factors for similarly aged individuals (HR: 1.49 and 1.82, respectively; P ≤ 0.005 for both). In 2,353 participants without CVD, TXB-M were associated with cardiovascular mortality in ASA nonusers (adjusted HR: 3.04; 95% CI: 1.29-7.16) but not in ASA users, while ASA use was associated with all-cause mortality in those with low (adjusted HR: 1.46; 95% CI: 1.14-1.87) but not elevated TXB-M.
CONCLUSIONS
Systemic thromboxane generation is an independent risk factor for all-cause and cardiovascular mortality irrespective of ASA use, and its measurement may be useful for therapy modification, particularly in those without CVD.
Topics: Aged; Aspirin; Cardiovascular Diseases; Creatinine; Female; Humans; Male; Middle Aged; Thromboxane B2; Thromboxanes
PubMed: 35660296
DOI: 10.1016/j.jacc.2022.04.034 -
The American Journal of Medicine Jan 2005
Topics: Disease Progression; Electrocardiography; Humans; Hypertension, Portal; Hypertension, Pulmonary; Liver Cirrhosis; Male; Middle Aged; Thromboxane A2; Thromboxane B2; Thromboxanes
PubMed: 15639216
DOI: 10.1016/j.amjmed.2004.11.007 -
Current Medicinal Chemistry May 2004Prostacyclin (PGI(2)) is a potent endogenous inhibitor of platelet function and possesses a strong vasodilator effect. Furthermore, prostacyclin is currently presented... (Review)
Review
Prostacyclin (PGI(2)) is a potent endogenous inhibitor of platelet function and possesses a strong vasodilator effect. Furthermore, prostacyclin is currently presented as the physiologic antagonist of thromboxane A(2)(TXA(2)), which exhibits pro-aggregatory and vasoconstrictor properties. So, the balance between PGI(2) and TXA(2) production is crucial for the cardiovascular system. Indeed, an imbalance in the production or effect of these products is deleterious for the circulatory system and can lead to characterized vascular diseases such as hypertension, stroke, atherosclerosis or myocardial infarction. Although the biological effects of PGI(2) are considered to be clinically useful, its use as therapeutic agent is largely limited by both its chemical and metabolic instability. Actually, several prostacyclin agonists have been synthesized and pharmacologically evaluated. Among these, some have been clinically evaluated as therapeutic agents in several vascular diseases. This review focuses on the latest chemical and pharmacological developments in the field of the prostacyclin agonists.
Topics: Cardiovascular System; Enzyme Inhibitors; Epoprostenol; Humans; Molecular Structure; Thromboxane A2; Thromboxanes
PubMed: 15134517
DOI: 10.2174/0929867043365279