LXR as a novel antithrombotic target

Abstract

Liver X receptors (LXRs) are transcription factors involved in the regulation of cholesterol homeostasis. LXR ligands have athero-protective properties independent of their effects on cholesterol metabolism. Platelets are involved in the initiation of atherosclerosis and despite being anucleate express nuclear receptors. We hypothesized that the athero-protective effects of LXR ligands could be in part mediated through platelets and therefore explored the potential role of LXR in platelets. Our results show that LXR-␤ is present in human platelets and the LXR ligands, GW3965 and T0901317, modulated nongenomically platelet aggregation stimulated by a range of agonists. GW3965 caused LXR to associate with signaling components proximal to the collagen receptor, GPVI, suggesting a potential mechanism of LXR action in platelets that leads to diminished platelet responses. Activation of platelets at sites of atherosclerotic lesions results in thrombosis preceding myocardial infarction and stroke. Using an in vivo model of thrombosis in mice, we show that GW3965 has antithrombotic effects, reducing the size and the stability of thrombi. The atheroprotective effects of GW3965, together with its novel antiplatelet/thrombotic effects, indicate LXR as a potential target for prevention of athero-thrombotic disease. (Blood. 2011;117(21):5751-5761) IntroductionLiver X receptors (LXRs) belong to the nuclear receptor superfamily, and their natural ligands, oxysterols, are cholesterol derivatives. 1 LXRs play key roles in cholesterol homeostasis by regulating the transcription of genes, such as cytochrome P450 7␣-hydroxylase 1 (Cyp7a1) and apoliprotein E (ApoE), involved in cholesterol catabolism to bile acids 2,3 and cholesterol efflux back to the liver, 4-6 respectively. LXRs have also been shown to have anti-inflammatory 7,8 and athero-protective effects after ligand stimulation. 9,10 Platelets are anucleate blood cells with a central role in hemostasis but are also involved in inflammation and atherosclerosis. [11][12][13][14] Their primary function is to prevent hemorrhage at sites of vascular injury, where exposed extracellular matrix proteins, such as collagen, interact with platelet surface receptors, resulting in platelet activation, aggregation, and thrombus formation. Although platelets are essential for the preservation of vascular integrity, inappropriate platelet activation, for example, at sites of atherosclerotic lesions, causes arterial thrombosis, leading to ischemic stroke and myocardial infarction, 2 of the main causes of morbidity and mortality in the industrialized world. 15 Low-density lipoprotein is the main therapeutic target for the prevention of atherothrombosis, 16 and low-density lipoprotein-lowering medications, such as statins, appear additionally to display antiplatelet actions. 17,18 Platelet function is also affected by cholesterol derivatives, although there is no consensus on whether these molecules have inhibitory or activatory roles. 19 The initial entrapment of platelets on subendothelial c...

Liver X receptor β activation induces pyroptosis of human and murine colon cancer cells

“…First, LXR ligands present anti-thrombic effects, through interaction of LXRb with Syk, PLC-g2 and peroxisome proliferator-activated receptor-g leading to the regulation of platelet functions. 19 Second, Hozoji et al described that in THP-1 cells, LXRb is associated with ATP-binding cassette transporter A1 (ABCA1) at the plasma membrane level and that under agonist treatment, LXRb dissociates from ABCA1 to promote cholesterol efflux and translocates to the nucleus to exert its transcriptional activity. 20,21 The cytoplasmic and sub-membrane localization of LXRb could account for its interaction with the intra-cellular C-terminal domain of pannexin 1.…”

Antithrombotic actions of statins involve PECAM-1 signaling

“…37,38 Briefly, the DIOC 6 -labeled human citrated blood was preincubated with vehicle control or increasing concentrations of statins and perfused over a collagen-coated Vena8 BioChip (Cellix Ltd) at a shear rate of 20 dyne/cm 2 . Z-stack images of thrombi were obtained for every 30 seconds for up to 10 minutes using a Nikon Eclipse microscope (TE2000-U; Nikon Instruments).…”

Isoform-Specific Regulation of a Steroid Hormone Nuclear Receptor by an E3 Ubiquitin Ligase inDrosophila melanogaster

“…The regulated activity of these receptors has a widespread effect on multiple aspects of development. For example, in mammals, they regulate cholesterol, osteoclast differentiation and triglyceride metabolism, and their impaired function leads to cardiovascular, bone, metabolic, and, possibly, Alzheimer's diseases (Patel and Forman 2004; Beaven and Tontonoz 2006;Mark et al 2006;Robertson et al 2006;Xiong et al 2008;Spyridon et al 2011 The EcR gene of Drosophila produces three protein isoforms (EcRA, EcRB1, and EcRB2) by using two promoters and alternative splicing (Talbot et al 1993). The three isoforms are able to heterodimerize USP and share the same carboxy terminus, which includes the hormone-binding and DNA-binding domains, while the amino termini are unique to each isoform.…”

“…The regulated activity of these receptors has a widespread effect on multiple aspects of development. For example, in mammals, they regulate cholesterol, osteoclast differentiation and triglyceride metabolism, and their impaired function leads to cardiovascular, bone, metabolic, and, possibly, Alzheimer's diseases (Patel and Forman 2004;Beaven and Tontonoz 2006;Mark et al 2006;Robertson et al 2006;Xiong et al 2008;Spyridon et al 2011).…”