14,169 research outputs found

    Role of prostacyclin in pulmonary hypertension

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    Date of Acceptance: 11/12/2014 This is an open access article distributed under the terms of the Creative Commons Attribution license CC BY-4.0, which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited.Prostacyclin is a powerful cardioprotective hormone released by the endothelium of all blood vessels. Prostacyclin exists in equilibrium with other vasoactive hormones and a disturbance in the balance of these factors leads to cardiovascular disease including pulmonary arterial hypertension. Since it’s discovery in the 1980s concerted efforts have been made to make the best therapeutic utility of prostacyclin, particularly in the treatment of pulmonary arterial hypertension. This has centred on working out the detailed pharmacology of prostacyclin and then synthesising new molecules based on its structure that are more stable or more easily tolerated. In addition, newer molecules have been developed that are not analogues of prostacyclin but that target the receptors that prostacyclin activates. Prostacyclin and related drugs have without doubt revolutionised the treatment and management of pulmonary arterial hypertension but are seriously limited by side effects within the systemic circulation. With the dawn of nanomedicine and targeted drug or stem cell delivery systems it will, in the very near future, be possible to make new formulations of prostacyclin that can evade the systemic circulation allowing for safe delivery to the pulmonary vessels. In this way, the full therapeutic potential of prostacyclin can be realised opening the possibility that pulmonary arterial hypertension will become, if not curable, a chronic manageable disease that is no longer fatal. This review discusses these and other issues relating to prostacyclin and its use in pulmonary arterial hypertensionPeer reviewedFinal Published versio

    The role of endothelin-1 in pulmonary arterial hypertension.

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    Pulmonary arterial hypertension (PAH) is a rare but debilitating disease, which if left untreated rapidly progresses to right ventricular failure and eventually death. In the quest to understand the pathogenesis of this disease differences in the profile, expression and action of vasoactive substances released by the endothelium have been identified in patients with PAH. Of these, endothelin-1 (ET-1) is of particular interest since it is known to be an extremely powerful vasoconstrictor and also involved in vascular remodelling. Identification of ET-1 as a target for pharmacological intervention has lead to the discovery of a number of compounds that can block the receptors via which ET-1 mediates its effects. This review sets out the evidence in support of a role for ET-1 in the onset and progression of the disease and reviews the data from the various clinical trials of ET-1 receptor antagonists for the treatment of PAH

    Diverse pharmacology of prostacyclin mimetics: Implications for pulmonary hypertension

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    Pulmonary arterial hypertension (PAH) is a progressive vascular remodelling disease where patients ultimately die from heart failure. Increased production of vasoconstrictors (endothelin-1 and thromboxane A2) accompanied by loss of prostacyclin, nitric oxide (NO), bone morphogenetic protein receptor type 2 (BMPR2) and TASK-1 combine to cause endothelial apoptosis, smooth muscle hyperactivity and thickening of the blood vessel wall. Prostacyclin remains the most efficacious treatment for PAH, and several prostacyclin analogues are approved for use via different administration routes. They act as vasodilators but potently inhibit platelet aggregation, cell proliferation and inflammation. The pharmacology of each prostacyclin (IP) receptor agonist is distinct, with other targets contributing to their therapeutic and side-effect profile, including prostanoid EP1, EP3, EP2 and DP1 receptors, alongside peroxisome proliferator-activated receptors (PPARs), to which prostacyclin and some analogues directly bind. To improve selectivity, selexipag, a non-prostanoid was developed, whose only significant biological target is the IP receptor, but is a partial agonist in cyclic AMP assays and has no anti-aggregatory properties in vivo. Prostanoid receptor expression profiles in the normal and diseased lung demonstrate loss of the IP receptor and upregulation of EP2 and EP3 receptors in PAH, affecting the action of prostacyclin mimetics in different ways. We discuss how prostacyclins might rescue BMPR2 and TASK-1 dysfunction and the importance of EP2 receptors as negative modulators of vascular tone, proliferation and fibrosis. Alongside DP1 and EP4 receptors, they have specific roles in veins and airways. Whether drugs selective for the IP receptor confer a superior or reduced therapeutic benefit remains an important clinical question as do the role of platelets in PAH

    A polymer coated cicaprost-eluting stent increases neointima formation and impairs vessel function in the rabbit iliac artery

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    Drug-eluting stents have been successful in reducing in-stent restenosis but are not suitable for all lesion types and have been implicated in causing late stent thrombosis due to incomplete regeneration of the endothelial cell layer. In this study we implanted stents coated with cicaprost, a prostacyclin analogue with a long plasma half-life and antiproliferative effects on vascular smooth muscle cells, into the iliac arteries of rabbits. At 28-day follow-up we compared neointima formation within the stented vessels and vascular function in adjacent vessels, to assess if cicaprost could reduce restenosis without impairing vessel function. Arteries implanted with cicaprost eluting stents had significantly more neointima compared to bare metal stents. In adjacent segments of artery, endothelium-dependent relaxation was impaired by the cicaprost-eluting stent but vasodilation to an endothelium-independent vasodilator was maintained. We conclude that the presence of the polymer and sub-optimal release of cicaprost from the stent may be responsible for the increased neointma and impaired functional recovery of the endothelium observed. Further experiments should be aimed at optimising release of cicaprost and exploring different stent polymer coatings

    The mechanistic basis for prostacyclin action in pulmonary hypertension

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    Pulmonary arterial hypertension (PAH) is a progressive disease of the small pulmonary arteries in which patients suffer from elevated pulmonary arterial pressure, right ventricular failure and a reduction in gas exchange. Left untreated the median survival from diagnosis is ~2.8 years, though outcome is significantly worse if patients have underlying pulmonary fibrosis or scleroderma. Injury to the endothelium probably initiates the disease process, with increased production of vasoconstrictors (endothelin and thromboxane) and growth factors accompanying the loss of vasodilator and anti-platelet agents, prostacyclin and nitric oxide, which results in vascular remodelling. To date prostacyclin therapy still remains the most efficacious treatment for PAH, although its short half-life and cumbersome delivery (continuous infusion) meant analogues with improved stability and alternative routes of delivery were developed. Classically, prostacyclin agents are thought to produce haemodynamic and anti-proliferative effects through prostacyclin (IP) receptors coupled to cyclic AMP generation, though other prostanoid receptors may contribute (EP2, EP4) or counterbalance (EP1, EP3) these responses. Increasing evidence suggests peroxisome proliferator-activated receptors (PPARs) are also cellular targets for prostacyclin agonists, regulating cell growth, inflammation and apoptosis through these transcription factors. Activation involves ligand binding and/or membrane receptors but probably not cyclic AMP. Here we discuss recent advances in our understanding of PPARs and how they may represent an important therapeutic target in PA

    The molecular genetics and cellular mechanisms underlying pulmonary arterial hypertension

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    Pulmonary arterial hypertension (PAH) is an incurable disorder clinically characterised by a sustained elevation of mean arterial pressure in the absence of systemic involvement. As the adult circulation is a low pressure, low resistance system, PAH represents a reversal to a foetal state. The small pulmonary arteries of patients exhibit luminal occlusion resultant from the uncontrolled growth of endothelial and smooth muscle cells. This vascular remodelling is comprised of hallmark defects, most notably the plexiform lesion. PAH may be familial in nature but the majority of patients present with spontaneous disease or PAH associated with other complications. In this paper, the molecular genetic basis of the disorder is discussed in detail ranging from the original identification of the major genetic contributant to PAH and moving on to current next-generation technologies that have led to the rapid identification of additional genetic risk factors. The impact of identified mutations on the cell is examined, particularly, the determination of pathways disrupted in disease and critical to pulmonary vascular maintenance. Finally, the application of research in this area to the design and development of novel treatment options for patients is addressed along with the future directions PAH research is progressing towards

    Consequences of altered eicosanoid patterns for nociceptive processing in mPGES-1-deficient mice

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    Cyclooxygenase-2 (COX-2)-dependent prostaglandin (PG) E2 synthesis in the spinal cord plays a major role in the development of inflammatory hyperalgesia and allodynia. Microsomal PGE2 synthase-1 (mPGES-1) isomerizes COX-2-derived PGH2 to PGE2. Here, we evaluated the effect of mPGES-1-deficiency on the noci-ceptive behavior in various models of nociception that depend on PGE2 synthesis. Surprisingly, in the COX-2-dependent zymosan-evoked hyperalgesia model, the nociceptive behavior was not reduced in mPGES-1-deficient mice despite a marked decrease of the spinal PGE2 synthesis. Similarly, the nociceptive behavior was unaltered in mPGES-1-deficient mice in the formalin test. Importantly, spinal cords and primary spinal cord cells derived from mPGES-1-deficient mice showed a redirection of the PGE2 synthesis to PGD2, PGF2α and 6-keto-PGF1α (stable metabolite of PGI2). Since the latter prostaglandins serve also as mediators of noci-ception they may compensate the loss of PGE2 synthesis in mPGES-1-deficient mice

    Estrogen, angiogenesis, immunity and cell metabolism: Solving the puzzle

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    Estrogen plays an important role in the regulation of cardiovascular physiology and the immune system by inducing direct effects on multiple cell types including immune and vascular cells. Sex steroid hormones are implicated in cardiovascular protection, including endothelial healing in case of arterial injury and collateral vessel formation in ischemic tissue. Estrogen can exert potent modulation effects at all levels of the innate and adaptive immune systems. Their action is mediated by interaction with classical estrogen receptors (ERs), ER\u3b1 and ER\u3b2, as well as the more recently identified G-protein coupled receptor 30/G-protein estrogen receptor 1 (GPER1), via both genomic and non-genomic mechanisms. Emerging data from the literature suggest that estrogen deficiency in menopause is associated with an increased potential for an unresolved inflammatory status. In this review, we provide an overview through the puzzle pieces of how 17\u3b2-estradiol can influence the cardiovascular and immune systems

    High throughput mutagenesis for identification of residues regulating human prostacyclin (hIP) receptor

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    The human prostacyclin receptor (hIP receptor) is a seven-transmembrane G protein-coupled receptor (GPCR) that plays a critical role in vascular smooth muscle relaxation and platelet aggregation. hIP receptor dysfunction has been implicated in numerous cardiovascular abnormalities, including myocardial infarction, hypertension, thrombosis and atherosclerosis. Genomic sequencing has discovered several genetic variations in the PTGIR gene coding for hIP receptor, however, its structure-function relationship has not been sufficiently explored. Here we set out to investigate the applicability of high throughput random mutagenesis to study the structure-function relationship of hIP receptor. While chemical mutagenesis was not suitable to generate a mutagenesis library with sufficient coverage, our data demonstrate error-prone PCR (epPCR) mediated mutagenesis as a valuable method for the unbiased screening of residues regulating hIP receptor function and expression. Here we describe the generation and functional characterization of an epPCR derived mutagenesis library compromising >4000 mutants of the hIP receptor. We introduce next generation sequencing as a useful tool to validate the quality of mutagenesis libraries by providing information about the coverage, mutation rate and mutational bias. We identified 18 mutants of the hIP receptor that were expressed at the cell surface, but demonstrated impaired receptor function. A total of 38 non-synonymous mutations were identified within the coding region of the hIP receptor, mapping to 36 distinct residues, including several mutations previously reported to affect the signaling of the hIP receptor. Thus, our data demonstrates epPCR mediated random mutagenesis as a valuable and practical method to study the structurefunction relationship of GPCRs. © 2014 Bill et al

    Selective COX-2 inhibitors and risk of myocardial infarction

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    Selective inhibitors of cyclooxygenase- 2 ( COX- 2, ` coxibs') are highly effective anti-inflammatory and analgesic drugs that exert their action by preventing the formation of prostanoids. Recently some coxibs, which were designed to exploit the advantageous effects of non- steroidal anti-inflammatory drugs while evading their side effects, have been reported to increase the risk of myocardial infarction and atherothrombotic events. This has led to the withdrawal of rofecoxib from global markets, and warnings have been issued by drug authorities about similar events during the use of celecoxib or valdecoxib/ parecoxib, bringing about questions of an inherent atherothrombotic risk of all coxibs and consequences that should be drawn by health care professionals. These questions need to be addressed in light of the known effects of selective inhibition of COX- 2 on the cardiovascular system. Although COX- 2, in contrast to the cyclooxygenase-1 ( COX- 1) isoform, is regarded as an inducible enzyme that only has a role in pathophysiological processes like pain and inflammation, experimental and clinical studies have shown that COX- 2 is constitutively expressed in tissues like the kidney or vascular endothelium, where it executes important physiological functions. COX- 2- dependent formation of prostanoids not only results in the mediation of pain or inflammatory signals but also in the maintenance of vascular integrity. Especially prostacyclin ( PGI(2)), which exerts vasodilatory and antiplatelet properties, is formed to a significant extent by COX- 2, and its levels are reduced to less than half of normal when COX- 2 is inhibited. This review outlines the rationale for the development of selective COX- 2 inhibitors and the pathophysiological consequences of selective inhibition of COX- 2 with special regard to vasoactive prostaglandins. It describes coxibs that are currently available, evaluates the current knowledge on the risk of atherothrombotic events associated with their intake and critically discusses the consequences that should be drawn from these insights. Copyright (C) 2005 S. Karger AG, Basel
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