thromboxane-a2 and Aortic-Aneurysm--Abdominal

Abdominal aortic aneurysm (AAA) is one of the leading causes of death in western countries. Surgery is still, at the present time, the sole treatment that has however a significant mortality and cost rate. Many pharmacological agents are under investigation aiming to reduce growth and prevent AAA rupture. These drugs target different pathological pathways and, notably, the excessive production of prostanoids by cyclooxygenases (COX). Intra-aneurysmal thrombus plays an adverse key role in the progression of AAA, platelets being a primary source of prostanoids as thromboxane A2.. In this review, we summarize studies targeting prostanoids production and down-stream pathways in cardiovascular diseases, and more specifically in AAA.. Various inhibitors of COX or antagonists of prostanoids receptors have been investigated in AAA animal models with conflicting results. In human AAA, only a few number of studies focused on anti-platelet therapy mostly using acetylsalicylic acid (aspirin, ASA), a COX1 inhibitor. Finally, we report preliminary promising results of a model of AAA in rats receiving a thromboxane A2 inhibitor, BM-573 that induced a reduction of aneurysmal growth.

Topics: Animals; Aortic Aneurysm, Abdominal; Cyclooxygenase Inhibitors; Disease Models, Animal; Humans; Prostaglandin Antagonists; Prostaglandins; Rats; Sulfonylurea Compounds; Thromboxane A2

The clinical use of niacin to treat dyslipidemic conditions is limited by noxious side effects, most commonly facial flushing. In mice, niacin-induced flushing results from COX-1-dependent formation of PGD₂ and PGE₂ followed by COX-2-dependent production of PGE₂. Consistent with this, niacin-induced flushing in humans is attenuated when niacin is combined with an antagonist of the PGD₂ receptor DP1. NSAID-mediated suppression of COX-2-derived PGI₂ has negative cardiovascular consequences, yet little is known about the cardiovascular biology of PGD₂. Here, we show that PGD₂ biosynthesis is augmented during platelet activation in humans and, although vascular expression of DP1 is conserved between humans and mice, platelet DP1 is not present in mice. Despite this, DP1 deletion in mice augmented aneurysm formation and the hypertensive response to Ang II and accelerated atherogenesis and thrombogenesis. Furthermore, COX inhibitors in humans, as well as platelet depletion, COX-1 knockdown, and COX-2 deletion in mice, revealed that niacin evoked platelet COX-1-derived PGD₂ biosynthesis. Finally, ADP-induced spreading on fibrinogen was augmented by niacin in washed human platelets, coincident with increased thromboxane (Tx) formation. However, in platelet-rich plasma, where formation of both Tx and PGD₂ was increased, spreading was not as pronounced and was inhibited by DP1 activation. Thus, PGD₂, like PGI₂, may function as a homeostatic response to thrombogenic and hypertensive stimuli and may have particular relevance as a constraint on platelets during niacin therapy.

Topics: 6-Ketoprostaglandin F1 alpha; Adenosine Diphosphate; Angioplasty, Balloon, Coronary; Animals; Aortic Aneurysm, Abdominal; Apolipoproteins E; Atherosclerosis; Blood Platelets; Carotid Artery Thrombosis; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Double-Blind Method; Endothelium, Vascular; Female; Humans; Hypertension; Male; Membrane Proteins; Mice; Mice, Knockout; Platelet Activation; Platelet Aggregation Inhibitors; Prostaglandin D2; Receptors, G-Protein-Coupled; Receptors, Immunologic; Receptors, LDL; Receptors, Nicotinic; Receptors, Prostaglandin; Thromboxane A2

Ruptured abdominal aortic aneurysm (AAA) contributes largely to aneurysm-related morbidity and mortality. An inflammatory gene, COX-2, was found to be widely expressed in AAA. However, the involvement of COX-2 metabolites and other inflammatory mediators in the disease and particularly in AAA rupture still needs elucidation. The purpose of the present study was to evaluate the secretion of inflammatory mediators and the expression of macrophages in aneurysms and determine their significance in ruptured AAA. Aortic tissue was harvested at time of aortic reconstructive surgery for the group of intact AAA (n=20) and ruptured AAA (n=10) or at time of organ harvest for normal aortic tissue (n=4). Aortic explant cultures were immediately established and the culture medium was collected after 72 h. Specific enzyme-linked immunoassorbent assays were used to quantify COX-2 metabolites and inflammatory cytokines. Inflammatory macrophage cells were also quantified in the corresponding aortic walls immunohistochemically. Differences in the secretory levels of inflammatory metabolites and the macrophage quantity in all groups were assessed. All three explant culture groups secreted detectable levels of studied COX-2 metabolites, including PGE(2), PGF(2alpha), PGI(2) and TxB(2) and inflammatory cytokines, including interleukin (IL)-1beta, IL-6, IL-8 and IL-10. The secretory levels of PGE(2), TXB(2) and IL-6 were highest in the ruptured AAA explant cultures and statistically higher than those in intact AAA cultures (p<0.05). The secretion of those inflammatory mediators and the local expression of macrophages in ruptured aneurysm probably reflects the active inflammatory processes in the aortic lesions. A means of modifying the inflammatory process in the wall of AAAs might play an important role in preventing aneurysm rupture.

Topics: Aged; Aortic Aneurysm, Abdominal; Aortic Rupture; Cyclooxygenase 2; Dinoprostone; Female; Humans; Inflammation Mediators; Interleukin-6; Macrophages; Male; Thromboxane A2; Tissue Culture Techniques

Abdominal aortic aneurysmectomy results in a general ischemia-reperfusion syndrome accompanied by an acute rise in mean pulmonary artery pressure (MPAP). Severe and sometimes fatal postoperative cardiopulmonary complications have been described.. This pilot study examined whether N-acetyl-cysteine (NAC), a precursor of the most important physiological antioxidant glutathione (reduced form: GSH; oxidized form: GSSG), or the hydroxyl radical scavenger mannitol (MAN) modifies these events. The patients received 150 mg/ kg b.m.NAC (n = 9) 30 minutes before infrarenal aortic clamping or 500 mg/kg b.m. MAN (n = 10) 10 minutes before declamping. 11 patients had no additional treatment (control).. In the control group, a significant increase in plasma levels of oxidized glutathione and lipid peroxides was observed after declamping. Additionally, a significant increase in plasma levels of the stable metabolites of thromboxane (TXB2) and prostacyclin (6-keto-PGF1 alpha) was measureable after declamping. There was a transient increase in MPAP and pulmonary vascular resistance (PVR), both of which returned to normal values within 20 minutes. Six hours after surgery, pulmonary dysfunction was manifest by increase in the intrapulmonary shunt fraction. Relative to the control group, NAC pretreatment led to a complete lack of changes in plasma lipid peroxide, thromboxane and prostacyclin levels after declamping; there was a significant increase in plasma GSH concentration persisting over a period of 12 hours. MPAP, PVR and Qs/QT values were unchanged. MAN pretreatment showed similar effects on the parameters obtained in the acute phase after declamping like the control group.. Pretreatment with NAC, but not mannitol, may help prevent ischemia-reperfusion syndrome following aortic clamping.

Topics: Acetylcysteine; Aged; Aortic Aneurysm, Abdominal; Epoprostenol; Free Radical Scavengers; Hemodynamics; Humans; Mannitol; Middle Aged; Oxidative Stress; Pilot Projects; Postoperative Complications; Reperfusion Injury; Thromboxane A2