Thromboxane receptor blockade improves the antiatherogenic effect of thromboxane A2 suppression in LDLR KO mice

Abstract

Suppression of thromboxane (Tx)A IntroductionAtherosclerosis is a complex and chronic inflammatory disease of the arterial wall influenced by diverse biochemical factors, including cytokines, chemokines, and growth factors. 1 One group of these mediators is represented by the prostanoids, a large family of bioactive lipids generating from arachidonic acid by the enzyme cyclooxygenase (COX). 2 The biosynthesis of prostanoids, specifically thromboxane A 2 (TxA 2 ) and prostacyclin (PGI 2 ), is grossly altered in human as well as in experimental atherosclerosis. 3,4 The increase in PGI 2 reflects in part the induction of both COX isoforms, COX-1 and COX-2, in the arterial wall. 5 However, most of the TxA 2 in this clinical setting derives from platelet COX-1 activation. 6 Both compounds may influence atherogenesis in different ways by modulating vascular inflammatory responses, cell growth, apoptosis, migration, and proliferation, processes that have all been implicated in atherosclerosis. 7 Cardioprotection from aspirin is widely attributed to its inhibitory effect on platelet COX-1-dependent TxA 2 formation. 8 Previously, we have provided evidence for the importance of COX-1-dependent TxA 2 formation in atherogenesis. Thus, targeted pharmacological inhibition of COX-1 by indomethacin as well as low-dose aspirin, but not COX-2 by nimesulide, retards atherogenesis in low-density lipoprotein receptor-deficient (LDLR KO) mice. 9-11 Consistent with our observation, selective inhibition of COX-1 enzyme activity and genetic deletion of COX-1 gene expression both reduce atherogenesis in another mouse model, the apolipoprotein E-KO (apoE-KO). 12,13 However, challenging this view, a recent report showed that COX-1 deficiency in bone marrow-derived cells worsens early atherosclerosis. 14 In general, although inhibition of COX-1 activity suppresses TxA 2 biosynthesis, it does not prevent the formation and, most importantly, the actions of other eicosanoids, such as hydroxyeicosatetraenoic acids and isoprostanes, which can both directly stimulate the receptor for TxA 2 and trigger proinflammatory reactions. 15 Interestingly, antagonism or genetic deletion of the TxA 2 receptor, called TP, reduces atherosclerosis in apoE-KO mice. 16,17 Taken together, the data would support the hypothesis that suppression of TxA 2 formation alone would not afford the most antiatherogenic effect because of the coincidental presence of nonconventional TP ligands, which could still favor a proinflammatory and proatherogenic vascular phenotype. Therefore, antagonism of the TP receptor associated with suppression of TxA 2 biosynthesis could augment the beneficial anti-inflammatory effects of COX-1 inhibition and be a more effective therapeutic approach to modulate atherogenesis than suppression of COX-1 activation alone.To this end, we treated LDLR KO mice with SC-560, a selective COX-1 inhibitor, 18 BM-573, a TP antagonist, 19 or a combination of the 2 drugs for 12 weeks during the development of atherogenesis. At the end of the treatments, we fou...

Beneficial Effect of Propofol on Arterial Adenosine Triphosphate-sensitive K+Channel Function Impaired by Thromboxane

“…Thromboxane A 2 reportedly plays a role in a variety of cardiovascular diseases, including myocardial infarction, cerebral vasospasm, hypertension, preeclampsia, and thrombotic disorders. 3,27,28 Accumulating findings demonstrated that ATP-sensitive K ϩ channels contribute to pathophysiological vasodilation during hypoxia, acidosis, and inflammation.…”

Macrophages: An elusive yet emerging therapeutic target of atherosclerosis

“…335 A selective COX-1 inhibitor, SC560, and TP antagonist, BM-573, or a combination of both showed protection in atherosclerosis development, in LDLR-deficient mice on a high-fat diet. 336 These observations indicate that a combinatorial therapy simultaneously targeting atherosclerosis and thrombosis can be of great value. However, recent findings have associated NSAID action with thrombosis and hypertension.…”

Could the thromboxane A2 pathway be a therapeutic target for the treatment of obstructive sleep apnea-induced atherosclerosis?

“…Numerous studies have suggested the interest of disrupting the TXA 2 signaling pathway to reduce atherosclerosis, either by inhibiting TXA 2 production [58][59][60], blocking TP receptors [61][62][63] or combining a TXA 2 synthesis inhibitor and a TP receptor antagonist [64][65][66]. Pharmacological inhibition of TXA 2 biosynthesis with non-steroidal anti-inflammatory preferential COX-1 inhibitor [58], low-dose aspirin [60] or a more selective COX-1 inhibitor (SC560) [59,64] reduced atherosclerosis lesion size.…”

“…Pharmacological inhibition of TXA 2 biosynthesis with non-steroidal anti-inflammatory preferential COX-1 inhibitor [58], low-dose aspirin [60] or a more selective COX-1 inhibitor (SC560) [59,64] reduced atherosclerosis lesion size. In ApoE −/− mice exposed to IH for 8 weeks, COX-1 inhibition by SC-560 during the last 4 weeks of IH exposure reduced the IH related progression of established atherosclerosis [8].…”