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)

With the development of subtype specific angiotensin II (Ang II) receptor antagonists and their introduction into the treatment of heart failure and hypertension, the regulation of the Ang II receptor with its subtypes AT1 and Ang T2 gains clinical importance. In cell cultures, the number of surface AT1 is clearly down-regulated by Ang II exposure. Down-regulation can be due to reversible internalization, to phosphorylation and to reduced synthesis and involves protein kinase C and phospholipase C mediated pathways. In this respect, the AT1 behaves as a typical G-protein coupled receptor. Aldosterone, cAMP, norepinephrine and extracellular glucose concentrations can contribute to AT1 regulation. There are very few data regarding the regulation of the subtype AT2, indicating modulation by a number of growth factors and by Ang II. In whole animal models receptor regulation deviates partially from cell cultures. In the rat, the two subtypes AT1A and AT1B are differentially regulated and the expression of subtypes is organ specific. In most experiments, including our own experiences, the AT1, in the adrenals was up-regulated by Ang II infusion and down-regulated by angiotensin converting enzyme inhibitors (ACEI) or Ang II receptor antagonists. Differing effects were observed in other organs. In humans, a number of studies seeking an association between Ang II levels, Ang II receptor regulation and physiological events have been conducted in platelets. In pregnant women, a negative correlation between plasma Ang II levels and Ang II binding and an association between receptor regulation and pregnancy-induced hypertension has been described.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of the angiotensin receptor subtypes in cell cultures, animal models and human diseases. 771 21

Major advances have been made that make it necessary to revise our thinking about the mechanisms of neuronal control to regulate cardiac functions, and that have implications for our understanding of cardiac diseases and their treatment. These advances include: function-specific pathways, co-transmitters, neuromodulators, sensory-efferent functions, changes in expression of autonomic nerves, neuroeffector junctions, and subtypes of neurotransmitter receptors. Studies of the molecular structure of the superfamily of the cation amine receptors have revealed that there might be a common ancestral G-protein coupled receptor to be derived from. Although noradrenaline effectively stimulates alpha 1- and alpha 2-adrenoceptors, they are completely different as a beta-adrenoceptors subfamily. The possible subtypes of beta 1-adrenoceptors are discussed in relation with the treatment of cardiac failure.
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PMID:[Neuronal control and neuroeffector transmission to regulate cardiac functions]. 810 Dec 34

Apoptosis as defined by contemporary science describes a form of cell death that involves discrete genetic and molecular programs, de novo protein expression and unique cellular phenotype. Evidence for the existence of apoptosis in the human heart has been reported in various cardiac diseases, including ischemic and non-ischemic heart failure, myocardial infarction and arrhythmias. Among the most potent stimuli that elicit cardiomyocyte apoptosis are: oxygen radicals (including NO), cytokines, (FAS/TNF alpha family of cytokines) and growth factors/energy deprivation. Several complex signal transduction pathways have been implicated in execution of cardiomyocyte apoptosis, including: Fas/TNF alpha receptors signaling, stress or mitogen activated protein kinases (SAPK/MAPK), sphingolipids metabolites (ceramide), G-protein coupled receptor (GPCR) signaling (G alpha i, G alpha q) and NF kappa B activation. Apoptosis of cardiac myocytes may contribute to progressive pump-failure, arrhythmias and cardiac remodeling. The recognition of numerous molecular targets associated with cardiomyocyte apoptosis that are amenable for pharmacologic manipulation, may provide novel therapeutic strategies for diverse cardiac ailments, as recently suggested by pharmacologic studies in experimental animals.
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PMID:Apoptosis in cardiac diseases--new opportunities for novel therapeutics for heart diseases. 1051 63

Apoptosis as defined by contemporary science describes a form of cell death that involves discrete genetic and molecular programs, de novo protein expression and unique cellular phenotype. Evidence for the existence of apoptosis in the human heart has been reported in various cardiac diseases, including ischemic and non-ischemic heart failure, myocardial infarction and arrhythmias. Among the most potent stimuli that elicit cardiomyocyte apoptosis are: oxygen radicals (including NO), cytokines, (e.g., TNFalpha, FAS) neurohormonal factors (angiotension II), cardiotoxic drugs (e.g., doxorubicin) and mechanical, stretch situations. Several complex signal transduction pathways have been implicated in execution of cardiomyocyte apoptosis. Most prominent are: 1) Tyrosine kinase receptors (TRK) induced signaling involving stress or mitogen activated protein kinases (SAPK/MARK) and sphingolipids metabolites (ceramide); 2) G-protein coupled receptor (GPCR) signaling (Galphai, Galphaq) and 3) NF(K) B activation. Apoptosis of cardiac myocytes may contribute to progressive pump-failure, arrhythmias and cardiac remodeling. The recognition of diverse molecular targets associated with cardiomyocyte apoptosis provide new opportunities for pharmacologic manipulation, that may lead to discovery and development of therapeutic strategies for treatment of heart failure, arrhythmias and myocardial infarction.
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PMID:Apoptosis--new opportunities for novel therapeutics for heart diseases. 1191 65

In addition to being a pro-inflammatory mediator, bradykinin is now recognized as a neuromediator and regulator of several vascular and renal functions. New breakthroughs point to unusual and atypical signalling pathways for a G-protein coupled receptor that could explain the anti-proliferative and anti-fibrogenic effects of bradykinin. The availability of transgenic and knock out animal models for bradykinin receptors or bradykinin-synthesizing or -catabolic enzymes confirms these cardiac and renal protective roles for this peptide system. Bradykinin receptors are involved in the therapeutic action of angiotensin-1 converting enzyme inhibitors that are used in the treatment of arterial hypertension, heart failure and diabetes. Nevertheless, recent evidence highlights dissimilar mechanisms in the regulation and function of these receptors between the central nervous system and peripheral tissues. Therefore, the development of more specific bradykinin receptor agonists or antagonists devoid of central actions seems to evolve as a new therapeutic approach.
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PMID:[Bradykinin receptors: towards new pathophysiological roles]. 1464 80

The actions of G-protein coupled receptor kinases (GRKs) critically regulate beta-adrenergic receptor (betaAR) signalling. In the cardiovascular system, the betaAR signalling pathway controls important responses of the heart such as the ability to contract (inotropy), the ability to contract faster (chronotropy) and the ability to relax (lusotropy). The observation that the betaAR kinase (betaARK1, also known as GRK2), the most abundant GRK in the heart, is increased in cardiovascular disease associated with impaired cardiac function, suggests that this molecule could have pathophysiological relevance in the setting of heart failure. Technological advances in the genetic engineering of mice have provided a powerful tool to study the physiological implications of altering GRK activity and expression in the heart. Recent studies have demonstrated that betaARK1 plays a key role in not only the regulation of myocardial signalling, but also in cardiac function and development. Importantly, targeting the activity of GRKs, and betaARK1 in particular, appears to represent a novel therapeutic strategy for the treatment of the failing heart. At present, gene therapy modalities are being tested which inhibit the activity of betaARK1 in the heart. This technology makes it possible to test directly whether betaARK1 inhibition in the setting of heart disease will improve the function of the compromised heart. Thus, these genetic approaches or the development of small molecule inhibitors of GRK activity, may lead to novel therapeutic approaches for cardiovascular disease.
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PMID:Therapeutic potential of G-protein coupled receptor kinases in the heart. 1599 14

Currently it is generally accepted that an individual's genetic makeup can modify the efficacy of drug treatment or the risk of adverse reactions. Although not a new concept, the availability of human genome sequence and rapid genotyping at variable loci in drug targets or metabolizing genes has provided new opportunities for the field termed "pharmacogenetics". Somewhat surprisingly, multiple studies have shown the existence of common variants (polymorphisms) in members of the G-protein coupled receptor superfamily, which constitute around 50% of all the targets of currently prescribed drugs. The beta1-adrenergic receptors (beta1ARs) are interesting candidates for pharmacogenetic studies in two complex cardiovascular disease, heart failure and hypertension, since they mediate the effects of catecholamines in the sympathetic nervous system. These receptors are involved in the progression and treatment (beta-blockers therapy) of both diseases, and have polymorphisms that show altered function or regulation as compared to their allelic counterparts in recombinant expression systems and genetically modified mice. These results have prompted prospective and retrospective clinical studies examining whether polymorphisms of these genes are risk factors, disease modifiers, or predictors of b-blocker response in heart failure and hypertension. To date, it appears that beta1AR variants are very likely one genetic component that defines responsiveness to beta-blockers in heart failure and hypertension. Altogether, results are promising, but discrepancies between studies require resolution before these polymorphisms can be utilized in practice. With the goal of personalizing therapy based on an individual's genetic makeup, additional adequately powered, multiethnic, multi-drug studies will be needed.
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PMID:Pharmacogenetics of beta1-adrenergic receptors in heart failure and hypertension. 1687 23

EVALUATION OF: Liggett SB, Cresci S, Kelly RJ et al.: A GRK5 polymorphism that inhibits beta-adrenergic receptor signaling is protective in heart failure. Nat. Med. 14, 510-517 (2008). beta-Adrenoceptor blockade therapy was developed for the treatment of hypertension but is now also a cornerstone in the treatment of heart failure. Based on the mechanisms of action and current knowledge of pathway signaling, Ligget et al. hypothesized that genetic variants within G-protein coupled receptor kinases might alter disease course and response to beta-adrenoceptor blockade therapy. Following a multistep approach, a common variant in GRK5 was identified as being important in vitro and in vivo (mouse model) in beta-adrenergic desensitization, and was epidemiologically related to survival and therapy response in African-Americans. Although such a variety of research approaches is appealing, owing to the large number of used methods readers remain puzzled on some issues because it is not possible to give all details of each individual study. Therefore, interpretation of the overwhelming amount of results is difficult. In an era of shifting emphasis from classic hypothesis driven pharmacogenetics to genome-wide association studies, this study shows that hypothesis driven translational research is still of high value, especially in phenotypes as investigated here.
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PMID:Protective effect of a GRK5 polymorphism on heart failure and its interaction with beta-adrenergic receptor antagonists. 1842 30

This article focuses on a newly discovered bioactive peptide, termed apelin, as it relates to the cardiovascular system. Apelin, through its G-protein coupled receptor, seems to primarily exert effects in blood pressure control, and may play a role in heart failure and in myocardial reperfusion injury. In addition, at least some of apelin's effects appear to stem from an interaction with the renin-angiotensin system. Apelin may provide a target for drug treatment of cardiovascular disease.
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PMID:The emerging role of apelin in cardiovascular disease and health. 1982 78

Hypertension represents a complex, multifactorial disease and contributes to the major causes of morbidity and mortality in industrialized countries: ischemic and hypertensive heart disease, stroke, peripheral atherosclerosis and renal failure. Current pharmacological therapy of essential hypertension focuses on the regulation of vascular resistance by inhibition of hormones such as catecholamines and angiotensin II, blocking them from receptor activation. Interaction of G-protein coupled receptor kinases (GRKs) and regulator of G-protein signaling (RGS) proteins with activated G-protein coupled receptors (GPCRs) effect the phosphorylation state of the receptor leading to desensitization and can profoundly impair signaling. Defects in GPCR regulation via these modulators have severe consequences affecting GPCR-stimulated biological responses in pathological situations such as hypertension, since they fine-tune and balance the major transmitters of vessel constriction versus dilatation, thus representing valuable new targets for anti-hypertensive therapeutic strategies. Elevated levels of GRKs are associated with human hypertensive disease and are relevant modulators of blood pressure in animal models of hypertension. This implies therapeutic perspective in a disease that has a prevalence of 65million in the United States while being directly correlated with occurrence of major adverse cardiac and vascular events. Therefore, therapeutic approaches using the inhibition of GRKs to regulate GPCRs are intriguing novel targets for treatment of hypertension and heart failure.
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PMID:Regulation of GPCR signaling in hypertension. 2006 Aug 96


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