Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Urotensin-II (U-II) is a vasoactive factor with pleiotropic effects. U-II exerts its activity by binding to a G-protein-coupled receptor termed UT. U-II and its receptor are highly expressed in the cardiovascular system. Increased U-II plasma levels have been reported in patients with cardiovascular disease of varying etiologies. We and others have shown that U-II and UT expression is elevated in both clinical and experimental heart failure and atherosclerosis. U-II induces cardiac fibrosis by increasing fibroblast collagen synthesis. In addition, U-II induces cardiomyocyte hypertrophy and increased vascular smooth muscle cell proliferation. We have shown that U-II antagonism using a selective U-II blocker, SB-611812 reduces neointimal thickening and increases lumen diameter in a rat restenosis model of carotid artery angioplasty. These findings suggest an important role for U-II in cardiovascular dysfunction and remodeling.
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PMID:Urotensin-II and cardiovascular diseases. 1713 7

Urotensin II (U-II) and urotensin II-related peptide (URP) are the endogenous ligands for the orphan G-protein-coupled receptor GPR14 now renamed UT. At the periphery, U-II and/or URP exert a wide range of biological effects on cardiovascular tissues, airway smooth muscles, kidney and endocrine glands, while central administration of U-II elicits various behavioral and cardiovascular responses. There is also evidence that U-II and/or URP may be involved in a number of pathological conditions including heart failure, atherosclerosis, renal dysfunction and diabetes. Because of the potential involvement of the urotensinergic system in various physiopathological processes, there is need for the rational design of potent and selective ligands for the UT receptor. Structure-activity relationship studies have shown that the minimal sequence required to retain full biological activity is the conserved U-II(4-11) domain, in particular the Cys5 and Cys10 residues involved in the disulfide bridge, and the Phe6, Lys8 and Tyr9 residues. Free alpha-amino group and C-terminal COOH group are not necessary for the biological activity, and modifications of these radicals may even increase the stability of the analogs. Punctual substitution of native amino acids, notably Phe6 and Trp7, by particular residues generates analogs with antagonistic properties. These studies, which provide crucial information regarding the structural and conformational requirements for ligand-receptor interactions, will be of considerable importance for the design of novel UT ligands with increased selectivity, potency and stability, that may eventually lead to the development of innovative drugs.
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PMID:Structure-activity relationships of urotensin II and URP. 1793 47

Urotensin II (U-II) is a vasoactive peptide with many potent effects in the cardiorenovascular system. U-II activates a G-protein-coupled receptor termed UT. UT and U-II are highly expressed in the cardiovascular and renal system. Patients with various cardiovascular diseases show high U-II plasma levels. It was demonstrated that elevated U-II plasma levels and increased UT expression seem to play a role in heart failure, end-stage renal disease and atherosclerosis. U-II induces potent changes in vascular tone regulation. In addition, U-II stimulates vascular smooth muscle cell proliferation and cardiomyocyte hypertrophy. Currently several pharmaceutical companies are developing compounds to control the U-II/UT system. There are preclinical and some clinical studies showing potential benefits of inhibiting U-II function in renal disease, heart failure, and diabetes. This article will review both pre- and clinical data concerning cardiorenovascular effects of U-II.
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PMID:Cardiorenovascular effects of urotensin II and the relevance of the UT receptor. 1793 30

The heart is richly innervated by sympathetic nerves, and both acute and chronic regulation of cardiac function via sympathetically released catecholamines acting on cardiomyocyte adrenergic receptors (ARs), is critical for circulatory homeostasis. Cardiomyocytes express alpha 1A- and alpha 1B-, and beta 1- and beta 2-AR subtypes, which are all members of the G-protein-coupled receptor superfamily that signal via interaction with heterotrimeric G-proteins. Cardiac function - both inotropy and chronotropy - is regulated predominantly by beta 1-AR. Activation of alpha 1-ARs also results in increased contractility, as well as changes in the electrophysiological properties and metabolic responses of the heart. Nonetheless, there is little evidence that cardiac alpha 1-ARs play a major functional role under normal physiological conditions. In pathological settings, alpha 1-ARs may function in a compensatory fashion to maintain cardiac inotropy when the beta-AR system is downregulated and uncoupled from G-proteins and effectors. In addition, as we consider here, recent evidence from clinical studies and from genetically engineered animal models indicates that alpha 1-ARs are importantly involved in both developmental cardiomyocyte growth, as well as pathological hypertrophy. In the presence of pressure overload or with myocardial infarction, activation of alpha 1-ARs, particularly the alpha 1A-subtype, also appears to produce important pro-survival effects at the level of the cardiomyocyte, and to protect against maladaptive cardiac remodelling and decompensation to heart failure.
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PMID:Cardiac alpha 1-adrenergic drive in pathological remodelling. 1803 91

Adrenergic receptor is one of the superfamilies of G-protein-coupled receptor. Its members are homologous in structure and diverse in function and are among the most pursued targets for drug development. Molecular pharmacological studies have established classification, structure, and function of adrenergic receptors approximately 100 years after Dr Langley had first referred to the philosophical concept of receptive substance. Molecular technology can identify mediating receptor subtype for each function. In this review, I focus on the current and evolving understanding of adrenergic receptor, especially relevant to the clinical settings such as heart failure and inverse agonism, and research topics such as desensitization and polymorphism, for all anesthesiologists.
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PMID:[Current aspects of research on adrenergic receptor]. 1821 3

Angiotensin II (Ang II) is considered the main final mediator of the renin-angiotensin-aldosterone system (RAAS). The actions of Ang II have been implicated in many cardiovascular conditions, such as hypertension, atherosclerosis, coronary heart disease, restenosis after injury, and heart failure. The Ang II type 1 receptor (AT(1)R), a G-protein-coupled receptor, mediates most of the physiological and pathophysiological actions of Ang II. This receptor is predominantly expressed in cardiovascular cells, such as vascular smooth muscle cells where it activates various signaling cascades leading to vascular remodeling and inflammation. Besides Ang II, aldosterone has emerged as an important component and mediator of the effects of the RAAS. Aldosterone-induced genomic effects mediated through binding to the mineralocorticoid receptor (MR), a member of the steroid hormone receptor superfamily, which functions as a ligand-dependent transcription factor, are characterized by a delay of minutes to hours corresponding to a long series of subcellular events that include gene activation and protein synthesis. Besides its well-known genomic actions, there is evidence of aldosterone-mediated rapid effects which lead to the activation of ion channels and other signaling pathways. Some of the effects of aldosterone occur through similar pathways as Ang II-induced signaling events. Indeed, recent studies suggest complex interactions between Ang II and aldosterone: it has become evident that aldosterone may influence the signaling or trafficking of the AT(1)R. Thus, growing evidence demonstrates the existence of cross-talk between Ang II and aldosterone which could potentially modulate Ang II signal transduction. These interactions between Ang II and aldosterone activate specific signaling pathways, sometimes in ways distinct from those that they induce on their own, one which may lead to pathogenic effects on target organs. Here we focus on recent findings and concepts that suggest the existence of novel signaling mechanisms whereby the cross-talk between Ang II and aldosterone plays a role in cardiovascular disease. We also discuss the importance of investigating Ang II/aldosterone cross-talk as a mean of developing new therapeutic strategies to combat cardiovascular disease.
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PMID:New insights on signaling cascades induced by cross-talk between angiotensin II and aldosterone. 1836 82

Beta-arrestin is a multifunctional adapter protein well known for its role in G-protein-coupled receptor (GPCR) desensitization. Exciting new evidence indicates that beta-arrestin is also a signaling molecule capable of initiating its own G-protein-independent signaling at GPCRs. One of the best-studied beta-arrestin signaling pathways is the one involving beta-arrestin-dependent activation of a mitogen-activated protein kinase cascade, the extracellular regulated kinase (ERK). ERK signaling, which is classically activated by agonist stimulation of the epidermal growth factor receptor (EGFR), can be activated by a number of GPCRs in a beta-arrestin-dependent manner. Recent work in animal models of heart failure suggests that beta-arrestin-dependent activation of EGFR/ERK signaling by the beta-1-adrenergic receptor, and possibly the angiotensin II Type 1A receptor, are cardioprotective. Hence, a new model of signaling at cardiac GPCRs has emerged and implicates classical G-protein-mediated signaling with promoting harmful remodeling in heart failure, while concurrently linking beta-arrestin-dependent, G-protein-independent signaling with cardioprotective effects. Based on this paradigm, a new class of drugs could be identified, termed "biased ligands", which simultaneously block harmful G-protein signaling, while also promoting cardioprotective beta-arrestin-dependent signaling, leading to a potential breakthrough in the treatment of chronic cardiac disease.
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PMID:Beta-arrestin-mediated signaling in the heart. 1883 25

Pulmonary hypertension (PH), a chronic disorder of the pulmonary vasculature, is characterized by progressive elevation in pulmonary artery pressure and the ultimate development of right-sided heart failure and death. Being a rapidly progressive disease with limited therapeutic options, the pathogenesis of PH is complex and multifactorial. The pathogenesis may result from a combination of vasoconstriction, inward vascular wall remodelling and in situ thrombosis that involves dysfunction of underlying cellular pathways and mediators. Among these, the activation of endothelin (ET) system has been shown to be important in the development and perpetuation of PH. Endothelin-1 (ET-1), a potent vasoconstrictor and mitogen, exerts its biological effects by binding to two G-protein-coupled receptor isoforms, endothelin A (ETA) receptor and endothelin B (ETB) receptor. These two receptors are nonredundant and unique because of distinct localization, unique binding locations and affinities for the endothelin peptide and activation of distinct signalling pathways. Importantly, there is now substantial evidence that direct antagonism of ET receptors that can block either ETA- or ETA- and ETB receptors can be beneficial for the treatment of PH in both preclinical and clinical setting. This review provides an overview of endothelin biology, various preclinical models that have been widely used to investigate the pathophysiology of PH as well as the individual roles of the ET receptors (ETA and ETB) and their regulation in disease pathogenesis. We also review current data on the use of selective and nonselective ET receptor antagonism in the preclinical PH models.
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PMID:Endothelin receptor antagonists in preclinical models of pulmonary hypertension. 1933 41

G-protein-coupled receptors (GPCRs) have been extremely successful drug targets for a multitude of diseases from heart failure to depression. This superfamily of cell surface receptors have not, however, been widely considered as a viable target in cancer treatment. In this study we show that a classical G(q/11)-coupled GPCR, the M(3)-muscarinic receptor, was able to regulate apoptosis through receptors that are endogenously expressed in the human neuroblastoma cell line, SH-SY5Y, and when ectopically expressed in Chinese hamster ovary (CHO) cells. Stimulation of the M(3)-muscarinic receptor was shown to inhibit the ability of the DNA-damaging chemotherapeutic agent, etoposide, from mediating apoptosis. This protective response in CHO cells correlated with the ability of the receptor to regulate the expression levels of p53. In contrast, stimulation of endogenous muscarinic receptors in SH-SY5Y cells did not regulate p53 expression but rather was able to inhibit p53 translocation to the mitochondria and p53 phosphorylation at serine 15 and 37. This study suggests the possibility that a GPCR can regulate the apoptotic properties of a chemotherapeutic DNA-damaging agent by regulating the expression, subcellular trafficking and modification of p53 in a manner that is, in part, dependent on the cell type.
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PMID:Regulation of p53 expression, phosphorylation and subcellular localization by a G-protein-coupled receptor. 1964 65

In conditions of stress, cardiomyocytes mount an adaptive response that attempts to normalize ventricular wall stress and maintain cardiac output. Prolonged stress overwhelms this protective response and leads to the apoptosis of cardiomyocytes and heart failure. The balance between the protective and apoptotic mechanisms is determined by a network of signaling pathways that can interact with the JAK/STAT pathway to effect the expression of either cardioprotective or pro-apoptotic genes. The activation of STAT3 affords cardioprotection, whereas activation of STAT1 is associated with apoptosis. Full and sustained activation of either pathway benefits from the cross-activation of the STATs by serine/threonine kinases in collateral signaling pathways. These pathways are activated by cytokines such as TNFalpha, Fas ligand and G-protein-coupled receptor ligands released by the ischemic myocardium. The interaction of these ligands with their respective signal transduction pathways and the nature of their interaction with the JAK/STAT pathway can influence the fate of stressed cardiomyocytes.
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PMID:Signaling networks regulating cardiac myocyte survival and death. 1970 35


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