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)

The primary cause of death following i.v. injection of the basic phospholipase A2 (PLA2) from Naja nigricollis venom has been attributed to its direct cardiotoxicity. In view of our recent findings that cardiac failure caused by the basic PLA2 from Naja m. mossambica is primarily due to hyperkalemia resulting from cellular damage and possibly also from hemolysis, the cause of death due to the basic PLA2 from Naja nigricollis was re-investigated. In the anesthetized mice and rats, the PLA2 (0.3 micrograms/g, i.v.) produced a transient hypotension followed by recovery and subsequently by cardiac failure with ECG changes suggestive of hyperkalemia, such as P-R prolongation, tall T-wave, biphasic QRS-T complex, low voltage of QRS, A-V block, etc. Analysis of blood chemistry revealed marked increases in the plasma levels of K+, CPK, LDH, GOT, GPT, inorganic phosphate and hemoglobin (probably a mixture of hemoglobin and myoglobin). In the atrial preparation, however, no marked cardiotoxicity was observed except for a slight negative inotropic effect at 30 micrograms/ml. When 200 micrograms of the enzyme was injected into the coronary circulation in the Langendorff preparation, also no marked cardiotoxic effect was observed except for a decrease (about 40%) of coronary flow. From these results, it is concluded that the primary cause of death following i.v. injection of the basic PLA2 from Naja nigricollis is apparently cardiac failure due to hyperkalemia, resulting from cellular damage and possibly also from hemolysis, rather than direct cardiotoxicity.
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PMID:Is direct cardiotoxicity the primary cause of death following i.v. injection of the basic phospholipase A2 from Naja nigricollis venom? 252 Mar 58

The Gaboon viper has acquired an impressive reputation which is at least partly unfounded. This handsome animal with such striking features is undoubtedly docile which accounts for the very low incidence of bite amongst humans. There are only six detailed clinical reports on the effect of bite and these are summarized in the review. The viper does indeed produce prodigious amounts of venom, but the toxicity, weight for weight, is rather low compared to other poisonous snakes. Venom extractions have been carried out on four snakes over a 13-year-period and the effects of this venom have been studied in a variety of experimental animals. Systemic envenomation is characterized by immediate abrupt hypotension, subsequent cardiac damage and dyspnoea. The individual venom components responsible for these effects have not been isolated but it seems likely that the two enzymes which have been studied extensively (phospholipase A2 and the thrombin-like enzyme, gabonase) do not contribute significantly to lethality. We propose three principal activities which give rise to the major signs of systemic envenomation. Haemorrhagin; causing widespread damage to microvasculature which leads to the pulmonary oedema and hence dyspnoea, and locally causes blistering. Cardiotoxin; a long-acting material causing cardiac muscle damage, arrhythmia and ultimately cardiac failure. Peripheral vasodilator; a short acting effect, operating either locally via bradykinin formation and/or unknown peptides or centrally on the vasomotor centre.
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PMID:The Gaboon viper (Bitis gabonica): its biology, venom components and toxinology. 639 43

The plant Crataegus monogyna has action against cardiac insufficiency, angina and arrhythmia. The anti-inflammatory properties of the cycloartenol fraction from this plant have been investigated. Chromatographic fractionation of the hexane extract of Crataegus monogyna Jacq. (Rosaceae) furnished a triterpene fraction containing cycloartenol as the main component (80.87%). The anti-inflammatory activity of the fraction was tested against hind-paw oedema induced by carrageenan in rats. At the highest oral dose (40 mg kg-1) inhibition was 61.5 and 52.5% at 3 and 5 h respectively. In the mouse carrageenan peritonitis test, the triterpene fraction given orally inhibited peritoneal leucocyte infiltration (41.9, 64.7 and 89.4% at 10, 20 and 40 mg kg-1, respectively). The fraction also showed weak inhibition of phospholipase A2 (PLA2) in-vitro. These results suggest that the fraction containing cycloartenol as the main component exerts an important anti-inflammatory action in-vivo by reducing the oedema.
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PMID:The effects of a triterpene fraction isolated from Crataegus monogyna Jacq. on different acute inflammation models in rats and mice. Leucocyte migration and phospholipase A2 inhibition. 923 56

Dopamine plays an important role in the regulation of renal sodium excretion. The synthesis of dopamine and the presence of dopamine receptor subtypes (D1A, D1B, as D1-like and D2, and D3 as D2-like) have been shown within the kidney. The activation of D1-like receptors located on the proximal tubules causes inhibition of tubular sodium reabsorption by inhibiting Na,H-exchanger and Na,K-ATPase activity. The D1-like receptors are linked to the multiple cellular signaling systems (namely, adenylyl cyclase, phospholipase C, and phospholipase A2) in the different regions of the nephron. Defective renal dopamine production and/or dopamine receptor function have been reported in human primary hypertension as well as in genetic models of animal hypertension. There may be a primary defect in D1-like receptors and an altered signaling system in the proximal tubules that lead to reduced dopamine-mediated effects on renal sodium excretion in hypertension. Recently, it has been shown in animal models that the disruption of either D1A or D3 receptors at the gene level causes hypertension in mice. Dopamine and dopamine receptor agonists also provide therapeutic potential in treatment of various cardiovascular pathological conditions, including hypertension. However, because of the poor bioavailability of the currently available compounds, the use of D1-like agonists is limited to the management of patients with severe hypertension when a rapid reduction of blood pressure is clinically indicated and in acute management of patients with heart failure. In conclusion, there is convincing evidence that dopamine and dopamine receptors play an important role in regulation of renal function, suggesting that a defective dopamine receptor/signaling system may contribute to the development and maintenance of hypertension. Further studies need to be directed toward establishing a direct correlation between defective dopamine receptor gene in the kidney and development of hypertension. Subsequently, it may be possible to use a therapeutic approach to correct the defect in dopamine receptor gene causing the hypertension.
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PMID:Renal dopamine receptor function in hypertension. 971 42

Endothelins (ETs) are 21-amino-acid peptides produced in many cells and tissues. The vascular ET system is represented mainly by ET-1 produced in endothelial cells. PreproET-1 gene expression is regulated by transactivating signals dependent on cooperative interaction of GATA-2 and AP-1 sites. ProET-1 is acted on by a furin-like enzyme to generate big ET-1, a 38-39-amino-acid peptide, which is converted to the mature 21-amino-acid peptide ET-1 by ET-converting enzyme (ECE) in endothelial cells, both intracellularly and on the cell membrane, and on the surface of underlying smooth muscle cells. The mature peptide ET-1 acts in a paracrine manner on smooth muscle cell ET(A) and ET(B) receptors to induce contraction and growth, and in an autocrine or paracrine manner on endothelial cells to induce production of the vasorelaxant and growth-inhibitory agents nitric oxide (NO) and prostacyclin. ET receptors are G-protein-coupled, resulting in activation of phospholipase C and generation of two second messengers, inositol triphosphate and diacylglycerol, which respectively stimulate calcium release and protein kinase C activation. Phospholipase D activation with generation of diacylglycerol, phospholipase A2 stimulation with release of arachidonic acid, activation of the Na+/H+ exchanger, and activation of tyrosine kinases and MAP kinases, are other pathways that contribute to contraction and growth induced by ET receptor stimulation. ET receptors may be downregulated by ET, especially under conditions in which large amounts of ET are being produced in the vasculature. This has been demonstrated in some models of experimental hypertension and in some forms of human hypertension. Some of the effects of angiotensin II, particularly growth of the smooth muscle media of blood vessels, have been shown under some conditions to be mediated by ET-1 via ET(A) receptors. Many ET-induced effects on smooth muscle cells can be blocked by ET(A)-selective ET antagonists, which makes possible an identification of the physiologic and pathophysiologic roles of the ET system in cardiovascular diseases such as hypertension, heart failure, atherosclerosis, coronary heart disease, restenosis after angioplasty, primary pulmonary hypertension, and other pathologic conditions.
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PMID:Vascular biology of endothelin. 988 41

Brain natriuretic peptide (BNP) gene expression accompanies cardiac hypertrophy and heart failure. The vasoconstrictor endothelin-1 (ET) may be involved in the development of these diseases. ET has also been shown to activate phospholipase A(2) (PLA(2)), and the resulting metabolites are important second messengers. We studied how ET and PLA(2) metabolites regulate BNP gene expression. The human BNP (hBNP) promoter (from -1818 to +100) coupled to a luciferase reporter gene was transferred into neonatal ventricular myocytes (NVMs), and luciferase activity was measured as an index of promoter activity. ET induced BNP mRNA in NVMs as assessed by Northern blot. It also stimulated the hBNP promoter, an effect completely inhibited by actinomycin D. To test the involvement of different PLA(2) isoforms, transfected cells were treated with various PLA(2) inhibitors before stimulation with ET. Only Ca(2+)-independent PLA(2) blockade prevented ET-stimulated hBNP promoter activity. The PLA(2) metabolite lysophosphatidic acid (LPA) also activated the hBNP promoter, but arachidonic acid itself did not. ET regulation of the hBNP promoter is pertussis toxin-sensitive. The nonreceptor tyrosine kinase Src and the small GTPase Rac mediate the effects of both ET and LPA in stimulation of the hBNP promoter. We studied the involvement of cis elements in ET-stimulated hBNP promoter activity. Deletion of BNP promoter sequences from -1818 to -408 and from -408 to -40 reduced the effect of ET by 60% and 80%, respectively. Moreover, ET-stimulated luciferase activity was reduced by 50% when the proximal GATA element was mutated. These data suggest that (1) ET activates the hBNP promoter through a transcriptional mechanism; (2) LPA, perhaps generated by iPLA(2), is involved in the effect of ET; (3) Src and Rac mediate ET and LPA stimulation of the hBNP promoter; and (4) ET regulation of the hBNP promoter targets both distal and proximal cis elements.
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PMID:Src and Rac mediate endothelin-1 and lysophosphatidic acid stimulation of the human brain natriuretic peptide promoter. 1123 Mar 22

The angiotensin AT(1) and AT(2) receptors have been cloned and characterised. Both are members of the serpentine receptor superfamily coupled to G proteins, but there is only 32% homology between the AT(1) and AT(2) receptors. The typical pharmacological features of AT(1) receptors are their selective affinity for biphenylimidazoles (typified by losartan) and their insensitivity to tetrahydroimidazopyridine (such as PD123319). In contrast, the AT(2) receptor has the opposite sensitivity for these two ligands. Genes located on chromosome 3 and X, respectively, encode the human AT(1) and AT(2) receptors. The signalling pathways of AT(1) and AT(2) are totally different. In addition to the classical signal transduction mechanisms (phospholipases C, D, A, voltage-dependent calcium channels and adenylate cyclase), the AT(1) receptor stimulates the phosphorylation of several tyrosine-containing proteins such as Jak 2, Stat 1 and mitogen-activated protein kinases. It also activates the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. The AT(1) receptor is responsible for the majority of the effects of angiotensin II: vasoconstriction, sodium re-absorption, cell proliferation, extracellular matrix formation, inflammatory response and oxidative stress. The AT(2) receptor is expressed abundantly in fetal tissues but at low density in adults. It is, however, upregulated in various pathological circumstances such as heart failure. In contrast to the AT(1) receptor, the signalling pathway of the AT(2) receptor does not induce an increase in inositol triphosphate and diacylglycerate formation with calcium mobilisation. Activation of the AT(2) receptor stimulates an intracellular mechanism involving various Tyr (tyrosine) and Ser (serine)/Thr (threonine) phosphatases, nitric oxide/cyclic guanosine monophosphate (cGMP) and phospholipase A(2). The effect of the AT(2) receptor counterbalances that of the AT(1) receptor: inactivation of mitogen-activated protein kinase (MAP), antiproliferation, promotion of apoptosis, opening of delayed-rectifier K(+) channels, closing of T-type Ca(2+) channels, stimulation of nerve differentiation and regeneration. It has been hypothesised that stimulation of the AT(2) receptor is part of the mechanism of action of the AT(1) receptor antagonists.
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PMID:[AT(1) and AT(2) angiotensin II receptors: key features]. 1203 84

Causal relationship between sodium and hypertension has been proposed and various changes in Na+,K+-ATPase (sodium pump) activity have been described in established primary hypertension. A number of direct vascular effects of estradiol have been reported, including its impact on the regulation of sodium pump activity and vasomotor tone. The effects of estradiol involve the activation of multiple signaling cascades, including phosphatydil inositol-3 kinase (PI3K) and p42/44 mitogen-activated protein kinase (p42/44(MAPK)). In addition, some of the effects of estradiol have been linked to activity of cytosolic phospholipase A(2) (cPLA(2)). One possible cardioprotective mechanism of estradiol involves of the interaction between estradiol and the rennin-angiotensin system (RAS). Elevated circulating and tissue levels of angiotensin II (Ang II) have been implicated in the development of hypertension and heart failure. The aim of our investigation was to elucidate the signaling mechanisms employed by estradiol and Ang II in mediating sodium pump, in vascular smooth muscle cells (VSMC). The aim of our investigation was to elucidate the signaling mechanisms employed by estradiol and Ang II in mediating sodium pump activity/expression in VSMC, with particular emphasis on PI3K/cPLA(2)/p42/44(MAPK) signaling pathways. Our primary hypothesis is that estradiol stimulates sodium pump activity/expression in VSMC via PI3K/cPLA(2)/p42/44(MAPK) dependent mechanism and, that impaired estradiol-stimulated sodium pump activity/expression in hypertensive rodent models (i.e. SHR), Ang II-mediated vascular impairment of estradiol is related to a decrease ability of estradiol to stimulate the PI3K/cPLA(2)/p42/44(MAPK) signaling pathways. An important corollary to this hypothesis is that in hypertensive state (i.e. SHR rats) the decreasing in ACE enzyme activity and/or AT1 receptor expression caused by administration of estradiol is accompanying with abrogated ability of Ang II to decrease IRS-1/PI3K association, and consequent PI3K/cPLA(2)/p42/44(MAPK) activity and associated sodium pump activity/expression. A clear characterization of how Ang II attenuates estradiol signaling may lead to a better understanding of the molecular mechanism(s) underlying pathophysiological conditions such as hypertension and to understanding how certain pathophysiological situations affect sodium pump activity/expression in VSMC.
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PMID:Hypothetical mechanism of sodium pump regulation by estradiol under primary hypertension. 1830 83

Necrotic cell death has long been considered an accidental and uncontrolled mode of cell death. But recently it has become clear that necrosis is a molecularly regulated event that is associated with pathologies such as ischemia-reperfusion (IR) injury, neurodegeneration and pathogen infection. The serine/threonine kinase receptor-interacting protein 1 (RIP1) plays a crucial role during the initiation of necrosis induced by ligand-receptor interactions. On the other hand, ATP depletion is an initiating factor in ischemia-induced necrotic cell death. Common players in necrotic cell death irrespective of the stimulus are calcium and reactive oxygen species (ROS). During necrosis, elevated cytosolic calcium levels typically lead to mitochondrial calcium overload, bioenergetics effects, and activation of proteases and phospholipases. ROS initiates damage to lipids, proteins and DNA and consequently results in mitochondrial dysfunction, ion balance deregulation and loss of membrane integrity. Membrane destabilization during necrosis is also mediated by other factors, such as acid-sphingomyelinase (ASM), phospholipase A(2) (PLA(2)) and calpains. Furthermore, necrotic cells release immunomodulatory factors that lead to recognition and engulfment by phagocytes and the subsequent immunological response. The knowledge of the molecular mechanisms involved in necrosis has contributed to our under-standing of necrosis-associated pathologies. In this review we will focus on the intracellular and intercellular signaling events in necrosis induced by different stimuli, such as oxidative stress, cytokines and pathogen-associated molecular patterns (PAMPs), which can be linked to several pathologies such as stroke, cardiac failure, neurodegenerative diseases, and infections.
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PMID:Molecular mechanisms and pathophysiology of necrotic cell death. 1847 20

Basic and clinical studies have suggested that inflammation predisposes to atrial fibrillation (AF). We assessed the association of 12 circulating inflammatory biomarkers (i.e., C-reactive protein, fibrinogen, interleukin-6, intercellular adhesion molecule-1, lipoprotein-associated phospholipase A2 [mass and activity], monocyte chemoattractant protein-1, myeloperoxidase, CD40 ligand, osteoprotegerin, P-selectin, and tumor necrosis factor receptor II) with incident AF in 2863 Framingham Offspring Study participants (mean age 60.7 years, SD = 9.4, 55% women). During follow-up (median 6 years), 148 participants (43% women) developed incident AF. In the multivariable proportional hazards models, the inflammatory biomarker panel was associated with incident AF (p = 0.03). With stepwise selection (p <0.01 for entry and retention), log-transformed osteoprotegerin was associated with incident AF (hazard ratio per SD 1.30, 95% confidence interval 1.08 to 1.56, p = 0.006). Adjusting for interim myocardial infarction or heart failure attenuated the association between osteoprotegerin and incident AF (hazard ratio 1.18, 95% confidence interval 0.98 to 1.43, p = 0.09). In conclusion, circulating osteoprotegerin concentration was significantly associated with incident AF in our community-based sample, possibly mediated by interim cardiovascular events.
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PMID:Relation of multiple inflammatory biomarkers to incident atrial fibrillation. 1957 26


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