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)

We previously showed that the human heart expresses all known P2X and P2Y receptors activated by extra-cellular adenine or uracil nucleotides. Despite evidence that, both in humans and rodents, plasma levels of ATP and UTP markedly increase during myocardial infarction, the differential effects mediated by the various adenine- and uracil-preferring myocardial P2 receptors are still largely unknown. Here, we studied the effects of adenine and uracil nucleotides on murine HL-1 cardiomyocytes. RT-PCR analysis showed that HL-1 cardiomyocytes express all known P2X receptors (except for P2X(2)), as well as the P2Y(2,4,6,14) subtypes. Exposure of cardiomyocytes to adenine nucleotides (ATP, ADP or BzATP) induced apoptosis and necrosis, as determined by flow-cytometry. Cell death was exacerbated by tumour necrosis factor (TNF)-alpha, a cytokine implicated in chronic heart failure progression. Conversely, uracil nucleotides (UTP, UDP and UDPglucose) had no effect 'per se', but fully counteracted the deleterious effects induced by adenine nucleotides and TNF-alpha, even if added to cardiomyocytes after beginning exposure to these cell death-inducing agents. Thus, exposure of cardiomyocytes to elevated concentrations of ATP or ADP in the presence of TNF-alpha contributes to cell death, an effect which is counteracted by uracil-preferring P2 receptors. Cardiomyocytes do not need to be 'primed' by uracil nucleotides to become insensitive to adenine nucleotides-induced death, suggesting the existence of a possible 'therapeutic' window for uracil nucleotides-mediated protection. Thus, release of UTP during cardiac ischaemia and in chronic heart failure may protect against myocardial damage, setting the basis for developing novel cardioprotective agents that specifically target uracil-preferring P2Y receptors.
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PMID:Opposite effects of uracil and adenine nucleotides on the survival of murine cardiomyocytes. 1841 95

Aim of the study was to investigate in dynamics peculiarities of hemostasis including platelet aggregation and activity of NADP-dependent dehydrogenases in platelets, as well as prevalence of resistance to aspirin in patients with functional class II-III chronic heart failure (CHF). We determined parameters of vascular thrombocytic and coagulative hemostasis, the state of intracellular metabolism of platelets as assessed by activity of NADP-dependent dehydrogenases in 46 men (age 45 - 72 years) with NYHA class II (n=16) and III (n=30) CHF before and in 12 - 14 days after coronary artery bypass grafting (CABG). After CABG all patients received aspirin (75 - 150 mg/day). Patients with ischemic CHF had moderate activation of intravascular coagulation, endotheliosis, elevation of fibrinogen and plasminogen levels. These processes were significantly augmented after CABG and were most pronounced in class II CHF. At the background of therapy with aspirin in 36 patients (78.3%) ADP and adrenaline induced platelet aggregation was reduced 2 - 3 times. In 10 patients (21.7%) aggregation remained at initial level or even increased what evidenced for resistance to aspirin. Among patients with functional classes II and III CHF portion of resistant to aspirin was 12.5 and 26.6%, respectively. In these patients most striking changes in intracellular metabolism of platelets were revealed. These changes manifested as derangements of energetic and plastic processes in the cell. Thus aspirin resistant patients with CHF comprise a group with risk of development of atherothrombosis of coronary arteries, arteriovenous grafts and arterial conduits.
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PMID:[Peculiarities of hemostasis, metabolic activity of platelets, and rate of aspirin resistance in patients with chronic heart failure after aorto-coronary bypass surgery]. 1872 37

Local control of ATP/ADP ratio is essential for efficient functioning of cellular ATPases. Since creatine kinase (CK) activity and mitochondrial content are reduced in heart failure (HF), and cardiomyocyte ultrastructure is altered, we hypothesized that these changes may affect the local energetic control of two major cardiac ATPases, the sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA) and the myosin ATPase. Heart failure was induced by aortic stenosis in rats. Electron microscopy confirmed that failing cardiomyocytes had intracellular disorganization, with fewer contacts between mitochondria and myofibrils. Despite normal SERCA protein content, spontaneous Ca2+ release measurements using Fluo-4 on saponin-permeabilized cardiomyocytes showed a lower SR loading in HF even when endogenous CK and mitochondria were fully activated. Similarly, in permeabilized fibres, SR Ca2+ loading supported by SR-bound CK and mitochondria was significantly reduced in HF (by 49% and 40%, respectively, 43% when both systems were activated, P < 0.05). Alkaline phosphatase treatment had no effect, but glycolytic substrates normalized calcium loading in HF to the sham level. The control by CK and mitochondria of the local ATP/ADP ratio close to the myosin ATPase (estimated by rigor tension) was also significantly impaired in HF fibres (by 32% and 46%, respectively). However, while the contributions of mitochondria and CK to local ATP regeneration were equally depressed in HF for the control of SERCA, mitochondrial contribution was more severely impaired than CK (P < 0.05) with respect to myofilament regulation. These data show that local energetic regulation of essential ATPases is severely impaired in heart failure, and undergoes a complex remodelling as a result of a decreased activity of the ATP-generating systems and cytoarchitecture disorganization.
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PMID:Local energetic regulation of sarcoplasmic and myosin ATPase is differently impaired in rats with heart failure. 1897 58

Mitochondrial dysfunction is implicated in the pathogenesis of diabetic cardiomyopathy, a common complication of diabetes. Adenosine nucleotide translocase (ANT) translocates ADP/ATP across the inner mitochondrial membrane. Our study aimed to test the hypothesis that overexpression of ANT1 in cardiomyocytes has cardioprotective effects in diabetic cardiomyopathy induced by streptozotocin (STZ). Mice specifically overexpressing murine ANT1 in the heart were generated using alpha-myosin heavy chain promoter. Expression of ANT1 mRNA and protein in hearts was characterized by real-time polymerase chain reaction and Western blot analysis. Five- to 6-month-old male transgenic mice and their age-matched wild-type littermates were subjected to type 1 diabetes induced by STZ. Six weeks later, haemodynamic measurement was performed to assess cardiac function. Ventricular mRNA expression of atrial natriuretic peptide, a molecular marker of heart failure, was characterized by RNase-protection assay. Both ANT1 mRNA and ANT1 protein were specifically overexpressed in the heart of transgenic mice. Heart weight was decreased and cardiac function was dramatically impaired in wild-type mice 6 weeks after induction of diabetes, but ANT1 overexpression prevented these significant changes. The mRNA expression level of atrial natriuretic peptide confirmed the haemodynamic findings, being upregulated in wild-type mice receiving STZ, but showing no statistical differences in ANT1 transgenic mice. Cardiomyocyte-restricted overexpression of ANT1 prevents the development of diabetic cardiomyopathy; therefore, accelerated ADP/ATP exchange could be a new promising target to treat diabetic cardiomyopathy.
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PMID:Myocardial overexpression of adenine nucleotide translocase 1 ameliorates diabetic cardiomyopathy in mice. 1894 56

Myocytes of the failing heart undergo impressive metabolic remodelling. The time line for changes in the pathways for ATP synthesis in compensated hypertrophy is: flux through the creatine kinase (CK) reaction falls as both creatine concentration ([Cr]) and CK activity fall; increases in [ADP] and [AMP] lead to increases in glucose uptake and utilization; fatty acid oxidation either remains the same or decreases. In uncompensated hypertrophy and in other forms of heart failure, CK flux and fatty acid oxidation are both lower; any increases in glucose uptake and utilization are not sufficient to compensate for overall decreases in the capacity for ATP supply and [ATP] falls. Metabolic remodelling is under transcriptional and post-transcriptional control. The lower metabolic reserve of the failing heart contributes to impaired contractile reserve.
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PMID:Energy metabolism in heart failure and remodelling. 1898 51

The article shows results obtained from 146 patients with acute coronary syndrome without ST-segment elevation and with concurrent heart failure stage IIA. All patients had profound changes of the hemostasis system. The use in a complex therapy klopidogrel medication, inhibitor of ADP-induced platelets aggregation considerably benefits state of blood coagulation properties: increases prothrombin time, INR-International normalized relation and APTT (activated partial thromboplastin time), decreases prothrombin index and fibrinogen quantity. Selective inhibitor of heart sinus node, ivabradin (koraksan) does not influence on hemogram indices and has positive influence on the course of the disease by lowering heart contraction frequency.
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PMID:[Effect of ivabradin and clopidogrel on platelet hemostasis indices in patients with acute coronary syndrome without ST-segment elevation and with concurrent cardiac insufficiency]. 1914 24

Exercise intolerance is a component of heart failure (HF) syndrome. We aimed to identify the defects in skeletal muscle mitochondria which may contribute to the development of peripheral myopathy. Subsarcolemmal (SSM) and interfibrillar (IFM) mitochondria were isolated from gastrocnemius muscle of control dogs (N=5) and dogs with pacing-induced HF (N=5). The measurement of integrated mitochondrial function (oxidative phosphorylation) and of individual activities of mitochondrial electron transport chain (ETC) complexes was complemented with the assessment of the amount and activity of the components of the phosphorylation apparatus. Both populations of skeletal muscle mitochondria isolated from HF have significantly decreased ADP-stimulated (state 3) respiratory rates with complex I, II and III substrates. The decrease in respiratory rates of skeletal muscle SSM are neither relieved upon collapsing the mitochondrial potential with an uncoupler nor increased in the presence of maximal ADP concentrations showing a defect in the ETC, which needs further investigation. In contrast, respiratory rates of skeletal muscle IFM from HF were relieved with the uncoupler and partially improved in the presence of maximal ADP concentrations. In these IFM, alterations in the phosphorylation apparatus were detected with a decreased amount of ANT isoform 2 and increased amount of isoform 1. The IFM dysfunction may be explained by this shift in ANT isoforms. In conclusion, pacing-induced HF causes a decrease in the oxidative phosphorylation of skeletal muscle mitochondria due to defects in the ETC and phosphorylation apparatus.
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PMID:Altered expression of the adenine nucleotide translocase isoforms and decreased ATP synthase activity in skeletal muscle mitochondria in heart failure. 1923 97

Crataegus (Hawthorn) fruit extracts (CE) are widely used for the treatment of various cardiovascular diseases (arrhythmias, heart failure, myocardial weakness, etc). Despite the fact that many of these diseases are associated with disturbances of the mitochondria, no data have been found on the effect of CE on their function. The aim of this study was to perform an oxygraphic investigation of the effect of CE (in concentration range from 70 ng/mL to 13.9 microg/mL of Crataegus phenolic compounds (PC)) and its several pure flavonoids on isolated rat heart mitochondria respiring on pyruvate+malate, succinate and palmitoyl-L-carnitine+malate. CE at doses under 278 ng/mL of PC had no effect on mitochondrial functions. At concentrations from 278 ng/mL to 13.9 microg/mL of PC, CE stimulated State 2 respiration by 11%-34% with all used substrates, and decreased the mitochondrial membrane potential by 1.2-4.4 mV measured with a tetraphenylphosphonium-selective electrode and H2O2 production measured fluorimetrically. Similar uncoupling effects on mitochondrial respiration were observed with several pure CE flavonoids. The highest CE concentration also slightly reduced the maximal ADP-stimulated and uncoupled respiration, which might be due to inhibition of the mitochondrial respiratory chain between flavoprotein and cytochrome c. Whether or not the uncoupling and other effects of CE on mitochondria may be realized in vivo remains to be determined.
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PMID:The effect of crataegus fruit extract and some of its flavonoids on mitochondrial oxidative phosphorylation in the heart. 1944 Oct 16

The ability of mitochondria to oxidatively synthesize ATP from ADP and inorganic phosphate is compromised in the failing heart. Specifically, the magnitude of the free energy at which ATP is synthesized in heart failure is diminished compared to control. However the causal mechanisms involved are not clearly understood. Here we used computer simulation to analyze the impact of reduction in three cytoplasmic metabolic pools that is observed with hypertrophic remodeling and heart failure. Our simulations, which are validated based on in vivo data on phosphate metabolites in both the healthy and diseased heart, predict that, given a prescribed reduction in the total adenine nucleotide pool, the pools of total creatine and total exchangeable phosphate are maintained at levels that maintain the ATP hydrolysis potential of the heart at near the normal physiological value.
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PMID:Creatine and phosphate pools are maintained at energetically optimal levels in the heart during hypertrophic remodeling and heart failure. 1996 69

Hypomagnesemia is common in hospitalized patients, especially in the elderly with coronary artery disease (CAD) and/or those with chronic heart failure. Hypomagnesemia is associated with an increased incidence of diabetes mellitus, metabolic syndrome, mortality rate from CAD and all causes. Magnesium supplementation improves myocardial metabolism, inhibits calcium accumulation and myocardial cell death; it improves vascular tone, peripheral vascular resistance, afterload and cardiac output, reduces cardiac arrhythmias and improves lipid metabolism. Magnesium also reduces vulnerability to oxygen-derived free radicals, improves human endothelial function and inhibits platelet function, including platelet aggregation and adhesion, which potentially gives magnesium physiologic and natural effects similar to adenosine-diphosphate inhibitors such as clopidogrel. The data regarding its use in patients with acute myocardial infarction (AMI) is conflicting. Although some previous, relatively small randomized clinical trials demonstrated a remarkable reduction in mortality when administered to relatively high risk AMI patients, two recently published large-scale randomized clinical trials (the Fourth International Study of Infarct Survival and Magnesium in Coronaries) failed to show any advantage of intravenous magnesium over placebo. Nevertheless, there are theoretical potential benefits of magnesium supplementation as a cardioprotective agent in CAD patients, as well as promising results from previous work in animal and humans. These studies are cost effective, easy to handle and are relatively free of adverse effects, which gives magnesium a role in treating CAD patients, especially high-risk groups such as CAD patients with heart failure, the elderly and hospitalized patients with hypomagnesemia. Furthermore, magnesium therapy is indicated in life-threatening ventricular arrhythmias such as Torsades de Pointes and intractable ventricular tachycardia.
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PMID:Magnesium and cardiovascular system. 2035 3


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