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Symposium Reports |
1 Cardiothoracic Pharmacology, National Heart and Lung Institute, Imperial College, Dovehouse Street, London SW3 6LY, UK
Abstract
The endothelium lines the luminal surface of every blood vessel, allowing it contact with circulating blood elements, as well as the underlying vascular smooth muscle layer. In healthy vessels, the endothelium expresses constitutive forms of nitric oxide synthase (NOSIII) and cyclo-oxygenase (COX-1), which produce the vasoactive hormones NO and prostacyclin, respectively. Both NO and prostacyclin relax blood vessels and inhibit platelet activation. The actions of prostacyclin are mediated by cell surface prostacyclin (IP) receptors and/or intracellular peroxisome proliferator-activated receptors (PPAR)β. The actions of NO are mediated predominately by activation of intracellular guanylyl cyclase, leading to the formation of cGMP. In platelets, the actions of NO and prostacyclin are synergistic, but in vessels their actions are additive. In diseased vessels, inducible forms of NOS (NOSII) and cyclo-oxygeanse (COX-2) are expressed in vascular smooth muscle, resulting in the release of large amounts of NO, prostacyclin and prostaglandin E2. The relative contribution of NOSII and COX-2 to vascular inflammation is still debated, but is likely to result in both protective and damaging responses. The relative contribution of constitutive forms of NOS and COX, as well as interactions between IP, PPARβ and guanylyl cyclase pathways in vessels and platelets, is discussed.
(Received 11 June 2007;
accepted after revision 21 September 2007; first published online 26 October 2007)
Corresponding author J. A. Mitchell: Cardiothoracic Pharmacology, Unit of Critical Care Medicine, National Heart and Lung Institute, Imperial College, Dovehouse Street, London SW3 6LY, UK. Email: j.a.mitchell{at}ic.ac.uk
Background
The endothelium lines the luminal surface of every blood vessel, forming a physical and metabolic barrier to circulating elements. The endothelium is an important endocrine organ, releasing a number of vasoactive hormones, including endothelin (ET)-1 (Yanagisawa et al. 1988), endothelium-derived hyperpolarizing factor (EDHF; Beny et al. 1987; Chen et al. 1988), nitric oxide (NO; Palmer et al. 1987) and prostacyclin (PGI2; Moncada et al. 1976). Endothelin-1 is a potent vasoconstrictor, and its biology has been reviewed extensively elsewhere (Marasciulo et al. 2006). Endothelium-derived hyperpolarizing factor is still a controversial subject of vascular biology, with debate surrounding its identify; the field of EDHF is reviewed elsewhere (Feletou & Vanhoutte, 2006). Nitric oxide and prostacyclin are coreleased from endothelial cells (de Nucci et al. 1988) of every vessel, and form a particular partnership in the regulation of vascular and platelet function. Parallels in how NO and prostacyclin are released, as well as how these hormones are sensed by cells of the cardiovascular system, are discussed in this article.
Synthesis of NO
Nitric oxide is synthesized by the enzyme NO synthase (NOS). There are three isoforms of NOS, which are classified as NOSI, NOSII and NOSIII (Ghosh & Salerno, 2003). Nitric oxide synthase I is found mainly in nerves and NOSII predominantly in inflammatory cells and at the site of inflammation, whereas NOSIII is found mainly in endothelial cells (Pollock et al. 1991). Nitric oxide synthase I and NOSIII are constitutively expressed and require calcium to activate them. Calcium is required to bind to calmodulin, which then associates with NOSI or NOSIII as part of the enzyme activation process (Pollock et al. 1991). Although a calcium–calmodulin (CaM)-regulated enzyme, it is clear that NOSIII is also highly regulated by post-translational lipid modifications, protein–protein interactions and protein phosphorylation (Sessa, 2004). Nitric oxide synthase II is inducible by cytokines and pathogen-associated molecular patterns (PAMPs), such as lipopolysaccharide (LPS; Mitchell et al. 2007), and is calcium independent. Nitric oxide synthase III in endothelial cells is a membrane-bound homodimer with a molecular weight of approximately 135 kDa (Pollock et al. 1991). Nitric oxide synthase III activity is facilitated by heat-shock protein 90, which acts as a chaperone (Garcia-Cardena et al. 1998). Nitric oxide is synthesized by NOS from the semi-essential amino acid L-arginine and molecular oxygen (Palmer et al. 1988). Tetrahydrobiopterin, NADPH, flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) are used as cofactors by NOSIII in the synthesis of NO (Pollock et al. 1993). L-Citrulline and water are the biproducts of the synthesis of NO from L-arginine.
Synthesis of prostacyclin
The first step in prostacyclin synthesis is the liberation of arachidonic acid from membrane-bound lipids via the enzymatic actions of phospholipase A2 (PLA2; Mitchell & Warner, 1999). In endothelial cells, phospholipase A2 activation is a calcium-dependent step. Once liberated, arachidonic acid is available for metabolism by cyclo-oxygenase (COX). Cyclo-oxygenase is present in two isoforms: COX-1 and COX-2. Cyclo-oxygenase-1, like NOSI or NOSIII, is constitutively expressed, whilst COX-2, like NOSII, is induced at sites of inflammation and/or by PAMPs (Mitchell & Warner, 2006). In healthy endothelial cells, COX-1 is the predominate isoform (Mitchell et al. 2006). Cyclo-oxygenase has two enzymatic activities: firstly, an oxygenase step forms prostaglandin (PG) G2; and secondly, a peroxidase step, which forms PGH2 from PGG2. Prostaglandin H2 is the substrate for a range of downstream prostaglandin synthase enzymes, including prostacyclin synthetase (PGIS), the actions of which result in the formation of prostacyclin. Endothelial cells are enriched in COX-1 and PGIS, which is why, when phospholipase A2 is activated, prostacyclin is the predominant metabolite made. By way of a comparison, it is important to note that in platelets, which also express predominantly COX-1, thromboxane is the principal product made. This is because platelets express mainly thromboxane synthase (Needleman et al. 1976), with negligible levels of PGIS.
Parallels in the synthesis of NO and prostacyclin by endothelial cells (see Fig. 1)
When endothelial cells are stimulated with agonists that increase intracellular calcium, they corelease NO and prostacyclin (de Nucci et al. 1988). Calcium is the common step, which is required in NO synthesis for the activation of NOSIII and in prostacyclin synthesis for the activation of phospholipase A2. It is important to note, however, that although NO and prostacyclin are coreleased by endothelial cells, the kinetics of release are different for these two hormones. Nitric oxide is released continuously (Mitchell et al. 1992; Harrington et al. 2007) while cells are activated, whereas prostacyclin is released in a transient manner (Luckhoff et al. 1988; Mitchell et al. 1992). The temporal differences in release of NO and prostacyclin result from the specific calcium requirements of NOSIII compared with phospholipase A2. Phospholipase A2 activation requires a high calcium burst resulting from the emptying of intracellular stores, which occurs only in the first minutes of cellular activation (Luckhoff et al. 1988). Following the initial burst of calcium peaks, cells retain elevated levels of calcium, albeit at lower concentrations, supported by entry to the cells from extracellular sources. Nitric oxide synthase III has a lower requirement for calcium than phospholipase A2 and is fully activated when intracellular calcium levels are supported by influx from extracellular stores.
Sensing mechanisms of NO
Once released by the endothelium, NO diffuses to the luminal side of the vessel, where it affects platelet and blood element functions, and to the abluminal side of the vessel, where it affects smooth muscle function. In platelets, NO inhibits adhesion and aggregation, thereby promoting blood fluidity and preventing thrombosis (Moncada & Higgs, 2006). In vascular smooth muscle, NO induces vasodilatation and inhibits vascular remodelling and smooth muscle cell proliferation. These effects of NO explain its cardioprotective function when released by the endothelium. In the case of platelets or vascular smooth muscle, the principal sensing pathway is guanylyl cyclase (Hanafy et al. 2001). There are three isoforms of guanylyl cyclase, namely soluble, particulate and cytoskeletal. Nitric oxide activates soluble guanylyl cyclase, present in the cytosol, causing an increase in intracellular cGMP, which activates protein kinase (PK) G, leading to reduced intracellular calcium and a reduction in cell activation (Hanafy et al. 2001). Whilst it is clear that guanylyl cyclase represents the predominant sensing pathway for NO in the vasculature, under some conditions NO may activate potassium channels, leading to vasodilatation (Tare et al. 1990). Finally, other signalling pathways that modulate the NO-induced responses have been suggested, such as S-nitrosylation of proteins, although these are unlikely to be of consequence in the sensing of NO in a healthy vessel.
Sensing pathways for prostacyclin
Like NO, prostacyclin is a central cardioprotective hormone. Its main effects are to inhibit platelet activation, reducing the risk of thrombosis, vasodilatation and reduction in vascular smooth muscle cell remodelling and cholesterol uptake (Nakayama, 2006). The actions of prostacyclin are, in many ways, opposite to thromboxane, which causes platelet activation, vasoconstriction and smooth muscle cells proliferation. For these reasons, the role of prostacyclin in the cardiovascular system is considered to be in balance with thromboxane. Drugs which selectively reduce thromboxane synthesis, such as low-dose aspirin, tip the balance in favour of prostacyclin and thereby create an antithrombotic state, protecting people from heart attack and stroke.
Prostacyclin acts predominantly on two receptor types: cell surface prostacyclin (IP) receptors and intracellular peroxisome proliferator-activated receptor (PPAR)β/
. There are a range of synthetic and naturally occurring prostanoid and non-prostanoid ligands which activate IP receptors and/or PPARβ (Table 1). The IP receptors are typical seven transmembrane-spanning G-protein-coupled receptors (Stitham et al. 2007), which are found on tissues throughout the body and are enriched on platelets and vascular smooth muscle cells. Activation of IP receptors results in G-protein-mediated activation of adenylate cyclase. Activation of adenylate cyclase leads to the formation of cAMP, which goes on to phosphorylate PKA, resulting ultimately in the reduction of calcium in most target cells (including vascular smooth muscle and platelets; Schwarz et al. 2001). It should be noted, however, that some evidence suggests that IP receptors may also couple other G-protein-mediated signalling pathways, although from our present knowledge, non-adenylyl cyclase sensing pathways of IP receptors are unlikely to be relevant in platelets and blood vessels (Stitham et al. 2007). At higher concentrations, prostacyclin may activate other cell surface prostaglandin receptors, although the predominant surface receptor for prostacyclin is thought to be IP.
The signalling pathways linked to PPARβ activation are more complex. Peroxisome proliferator-activated receptor β is a member of a family of three PPAR receptors, including PPAR
and PPAR
(Moraes et al. 2006). The PPARs exert some of their effects via an action on gene transcription and have an NH2-terminal domain that regulates activity, a DNA-binding domain that binds to the PPAR response element (PPRE) in the promoter region of target genes, a domain for a cofactor, and a COOH-terminal ligand-binding domain that determines ligand specificity (Moraes et al. 2006). The PPARs are bound to corepressor proteins when inactive. After stimulation by PPAR activators, PPARs dissociate from corepressors and recruit coactivators, which include a PPAR-binding protein and the steroid receptor coactivator-1, and heterodimerize with retinoid X receptor (RXR). This dimer then binds to PPRE on target genes to modulate gene transcription. Gene regulation by this mechanism is responsible for the actions of PPARs on carbohydrate and lipid metabolism, as well as many of their cardioprotective effects. The PPARs also exert numerous effects by interaction with different transcription factors and preventing transcription of pro-inflammatory genes. Thus, many of the well-documented beneficial effects of PPARs within the cardiovascular systems are associated with events that require the nucleus, consistent with their known mechanism of action.
Peroxisome proliferator-activated receptor β is the least studied of the PPARs. Selective agonists and genetically modified mice (PPARβ–/–; Michalik et al. 2001) have been generated, but there are still no antagonists, which makes study difficult. Work from our group has shown that activation of PPARβ, rather than IP receptors, mediates the inhibition of lung cell proliferation by the prostacyclin mimetic treprostinil sodium (Ali et al. 2006b). In addition, work from our group has shown that specific PPARβ agonists inhibit platelet aggregation (Ali et al. 2006a) by a mechanism independent of IP receptors (F. Ali & J. A. Mitchell, unpublished observations). We also found that PPARβ agonists act in synergy with IP receptor agonists to inhibit platelet aggregation (Ali et al. 2006a). These observations suggest that IP and PPARβ receptors are linked to separate complimentary signalling pathways and explain why prostacyclin is such a potent and efficacious inhibitor of platelet function. The role of PPARβ in the regulation of vascular tone is not known. However, preliminary data from our group suggest that it may inhibit contractile responses (Ali et al. 2005a), although the mechanism regulating this response is currently not known.
It is not immediately obvious how activation of PPARβ in platelets can result in inhibition of function, since PPAR receptors are nuclear receptors and affect function at the level of gene transcription. Platelets have no nuclei, which means that any effects seen there must be mediated by non-genomic pathways. Others have shown that rosiglitazone, which activates PPAR, inhibits platelet activation (Akbiyik et al. 2004), although no mechanism was put forward in that study. Work from our group also shows that statins (which activate PPAR and PPAR) or fibrates (which activate PPAR) inhibit platelet function via a PPAR-dependent mechanism (Ali et al. 2005b). Whilst a mechanism is not yet identified, there are two studies which may provide clues. Firstly, Bishop-Bailey's group have shown that ligands for RXR, another nuclear receptor which dimerizes with PPARs, inhibits platelet function by an interaction with Gq (Moraes et al. 2007). Secondly, in nucleated cells, PPAR has been shown to directly associate with protein kinase (PK) C, leading to repression of activity (Johann et al. 2007). Since platelet PKC is important for calcium signalling and activation, this pathway may potentially be involved in the sensing of prostacyclin via PPARβ in platelets.
Parallels in the sensing of NO and prostacyclin by blood vessels and platelets (see Fig. 2)
Both NO and prostacyclin are potent inhibitors of platelet activation and vasoconstriction. Nitric oxide and prostacyclin (via IP receptors) rely on the second messengers cGMP and cAMP, respectively, to mediate their effects. In platelets, NO and prostacyclin synergize with each other to inhibit aggregation (Botting & Vane, 1989), although the precise mechanism regulating this synergy is not completely understood. Recent work from our group shows that PPARβ, like IP agonists, synergizes with NO to inhibit platelet aggregation (Ali et al. 2006a).
Summary
The presence of a functional endothelium is critical to the maintenance of a healthy cardiovascular system. The endothelium forms a physical barrier to circulating elements. In addition, the endothelium forms an all-encompassing metabolic barrier that extends to all areas of the body. Nitric oxide and prostacyclin are arguably the most important cardioprotective hormones yet described. They are coreleased by endothelial cells and act in synergy to inhibit platelet activation, thereby limiting thrombosis. The close functional relationship between NO and prostacyclin means that if the release of one or other of these hormones is compromised, the cardiovascular system is put under significant strain and the risk of heart attack and stroke increase. The fields of NO and prostacyclin biology are now well established but there is still much to learn about how these two hormones act and interact in order for us to exploit their therapeutic potential fully.
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