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

This study examined the activity of discrete regions of the brain as assessed with histological localization and photodensitometric quantification of the metabolic enzyme hexokinase in a group of rats with coronary occlusion (HF) and in sham-operated control rats. Three weeks after surgery, the mean left ventricular end diastolic pressure and right atrial pressure were elevated, and left ventricular peak systolic pressure was decreased in the HF group compared with the sham group; these findings are also observed during heart failure. In addition, histological data indicated that there was a 37.6 +/- 2.8% outer and 40.8 +/- 3.1% inner infarct of the myocardium in the group of rats with HF (n = 6). Rats in the control group had no observable damage to the myocardium (n = 6). Accompanying these symptoms of heart failure were significant increases in hexokinase activity in the parvocellular (pPVN, 16.3%) and magnocellular (mPVN, 17.6%) divisions of the paraventricular nucleus of the hypothalamus, and in the locus ceruleus (LC, 17.1%). No changes in hexokinase activity were observed in the median preoptic area, supraoptic nucleus (SON), subfornical organ, or posterior hypothalamus. These results reinforce the idea that heart failure (with coronary occlusion) is associated with changes in specific areas in the brain and that metabolic alterations in the pPVN, mPVN, and LC are likely related to alterations in vasopressin production, blood volume regulation, and sympathoexcitation observed in the heart failure state.
 ...
PMID:Alterations in brain hexokinase activity associated with heart failure in rats. 823 66

1. A number of neurohumoral processes are activated in heart failure (HF), including an increase in the plasma concentration of noradrenaline. 2. Few studies have been performed to examine the role of the central nervous system (CNS) in the activation of sympathetic outflow during HF. In the present paper we review the limited studies performed to examine the role of the CNS in the activation of sympathetic outflow, with particular emphasis on our recent study that examined the activity of discrete regions of the brain as assessed by histological localization and photodensitometric quantification of the metabolic enzyme hexokinase during HF. 3. There were significant increases in hexokinase activity in the parvocellular (pPVN) and magnocellular (mPVN) divisions of the paraventricular nucleus of the hypothalamus and in the locus coeruleus (LC) in rats with HF. No changes in hexokinase activity were observed in the median preoptic area, supraoptic nucleus (SON) or posterior hypothalamus. 4. We conclude that HF is associated with changes in specific areas in the brain and that alterations in the activation of neurons in the pPVN, mPVN and LC are likely to be related to alterations in vasopressin production, blood volume regulation and sympathoexcitation observed in the HF state.
 ...
PMID:Neurohumoral activation in heart failure: role of paraventricular nucleus. 888 97

Coupling of ATP-generating with ATP-consuming processes is an essential component in the cardiac bioenergetics responsible for optimal myocardial function. Although a number of enzymatic systems have been implicated in securing proper intracellular energy communication, their integrative response in a failing myocardium has not been determined so far. Therefore, we measured catalytic activities of enzymes responsible for the communication between ATP-generating and ATP-consuming processes in ventricular samples obtained from normal dogs and dogs with tachycardia-induced heart failure. In the failing myocardium, phosphotransfer activities of creatine kinase, adenylate kinase, 3-phosphoglycerate kinase and pyruvate kinase, which collectively deliver ATP and remove ADP from myofibrillar ATPases, were depressed by 30, 21, 44 and 20%, respectively, when compared to normal controls. The activity of hexokinase, an enzyme which directs phosphoryls into the glycolytic phosphotransfer pathway, was unchanged. Also, the activity of glyceraldehyde-3-phosphate dehydrogenase, which may shuttle inorganic phosphate between ATPases and ATP-synthases, was not affected by heart failure. However, the CO2-hydration activity of carbonic anhydrase, which together with creatine kinase, is presumed responsible for removal of protons from ATPases, was diminished by 21%. As these enzymatic systems are collectively required for adequate delivery of high-energy phosphoryl to, and removal of end-products from, cellular ATPases, the cumulative deficit in their flux capacities may provide a bioenergetic basis for impaired contraction-relaxation in the failing heart.
 ...
PMID:Reduced activity of enzymes coupling ATP-generating with ATP-consuming processes in the failing myocardium. 1063 Jun 20

It was previously reported that inhibition of carnitine synthesis by 3-(2,2,2-trimethyl-hydrazinium) propionate (MET-88) restores left ventricular (LV) systolic and diastolic function in rats with myocardial infarction (MI). Preservation of the calcium uptake function of sarcoplasmic reticulum Ca2+-ATPase (SERCA2) is one of the possible mechanisms by which MET-88 alleviates hemodynamic dysfunction. To test this hypothesis, the effects of MET-88 on protein content of SERCA2 were evaluated using the same rat model of heart failure. Myocardial protein content of hexokinase, which is one of the key enzymes of glucose utilization, was also measured. Either MET-88 (MET-88 group) or a placebo (MI group) was administered for 20 days to rats with MI induced by coronary artery ligation. The control group underwent sham surgery (no ligation) and received placebo. In LV myocardial homogenates, the myocardial SERCA2 protein content was 32% lower (p<0.05) in the MI group than in the control group. However, in the MET-88 group myocardial SERCA2 content was the same as in the control group. Hexokinase I protein content was 29 % lower (p<0.05) in the MI group compared with the control. In contrast, hexokinase II protein content did not differ significantly among the three groups. Consequently, inhibition of carnitine synthesis ameliorates depression of SERCA2 and hexokinase I protein content which may reduce tissue damage caused by MI.
 ...
PMID:Inhibition of carnitine synthesis modulates protein contents of the cardiac sarcoplasmic reticulum Ca2+-ATPase and hexokinase type I in rat hearts with myocardial infarction. 1109 60

Sympathetic hyperactivity (SH) is a hallmark of heart failure (HF), and several lines of evidence suggest that SH contributes to HF-induced skeletal myopathy. However, little is known about the influence of SH on skeletal muscle morphology and metabolism in a setting of developing HF, taking into consideration muscles with different fiber compositions. The contribution of SH on exercise tolerance and skeletal muscle morphology and biochemistry was investigated in 3- and 7-mo-old mice lacking both alpha(2A)- and alpha(2C)-adrenergic receptor subtypes (alpha(2A)/alpha(2C)ARKO mice) that present SH with evidence of HF by 7 mo. To verify whether exercise training (ET) would prevent skeletal muscle myopathy in advanced-stage HF, alpha(2A)/alpha(2C)ARKO mice were exercised from 5 to 7 mo of age. At 3 mo, alpha(2A)/alpha(2C)ARKO mice showed no signs of HF and preserved exercise tolerance and muscular norepinephrine with no changes in soleus morphology. In contrast, plantaris muscle of alpha(2A)/alpha(2C)ARKO mice displayed hypertrophy and fiber type shift (IIA --> IIX) paralleled by capillary rarefaction, increased hexokinase activity, and oxidative stress. At 7 mo, alpha(2A)/alpha(2C)ARKO mice displayed exercise intolerance and increased muscular norepinephrine, muscular atrophy, capillary rarefaction, and increased oxidative stress. ET reestablished alpha(2A)/alpha(2C)ARKO mouse exercise tolerance to 7-mo-old wild-type levels and prevented muscular atrophy and capillary rarefaction associated with reduced oxidative stress. Collectively, these data provide direct evidence that SH is a major factor contributing to skeletal muscle morphological changes in a setting of developing HF. ET prevented skeletal muscle myopathy in alpha(2A)/alpha(2C)ARKO mice, which highlights its importance as a therapeutic tool for HF.
 ...
PMID:Sympathetic hyperactivity differentially affects skeletal muscle mass in developing heart failure: role of exercise training. 1917 49

Glycogen synthase kinase-3beta (GSK-3beta) is a multifunctional Ser/Thr kinase that plays important roles in necrosis and apoptosis of cardiomyocytes. A major mechanism of cell necrosis is the opening of the mitochondrial permeability transition pore (mPTP), which consists of multiple protein subunits, including adenine nucleotide translocase (ANT). The threshold for mPTP opening is elevated by phosphorylation of GSK-3beta at Ser9, which reduces activity of this kinase. How inactivation of GSK-3beta suppresses mPTP opening has not been fully understood, but evidence to date suggests that preservation of hexokinase-II in the mPTP complex, inhibition of cyclophilin-D-ANT binding, inhibition of p53 and inhibition of ANT into the mitochondria are contributory. GSK-3beta phosphorylation is a step to which multiple protective signaling pathways converge, and thus GSK-3beta phosphorylation is crucial in cardioprotection of a variety of interventions against ischemia/reperfusion injury. Apoptosis of cardiomyocytes by pressure overload or ischemia/reperfusion is also suppressed by inactivation of GSK-3beta, in which reduced phosphorylation of p53, heat shock factor-1 and myeloid cell leukemia sequence-1 and inhibition of Bax translocation might be involved. Considering predominant roles of GSK-3beta in cardiomyocyte death, manipulation of this protein kinase is a promising strategy for myocardial protection in coronary artery disease and heart failure.
 ...
PMID:GSK-3beta, a therapeutic target for cardiomyocyte protection. 1950 20

Poor skeletal muscle performance was shown to strongly predict mortality and long-term prognosis in a variety of diseases, including heart failure (HF). Despite the known benefits of aerobic exercise training (AET) in improving the skeletal muscle phenotype in HF, the optimal exercise intensity to elicit maximal outcomes is still under debate. Therefore, the aim of the present study was to compare the effects of high-intensity AET with those of a moderate-intensity protocol on skeletal muscle of infarcted rats. Wistar rats underwent myocardial infarction (MI) or sham surgery. MI groups were submitted either to an untrained (MI-UNT); moderate-intensity (MI-CMT, 60% Vo(2)(max)); or matched volume, high-intensity AET (MI-HIT, intervals at 85% Vo(2)(max)) protocol. High-intensity AET (HIT) was superior to moderate-intensity AET (CMT) in improving aerobic capacity, assessed by treadmill running tests. Cardiac contractile function, measured by echocardiography, was equally improved by both AET protocols. CMT and HIT prevented the MI-induced decay of skeletal muscle citrate synthase and hexokinase maximal activities, and increased glycogen content, without significant differences between protocols. Similar improvements in skeletal muscle redox balance and deactivation of the ubiquitin-proteasome system were also observed after CMT and HIT. Such intracellular findings were accompanied by prevented skeletal muscle atrophy in both MI-CMT and MI-HIT groups, whereas no major differences were observed between protocols. Taken together, our data suggest that despite superior effects of HIT in improving functional capacity, skeletal muscle adaptations were remarkably similar among protocols, leading to the conclusion that skeletal myopathy in infarcted rats was equally prevented by either moderate-intensity or high-intensity AET.
 ...
PMID:High- versus moderate-intensity aerobic exercise training effects on skeletal muscle of infarcted rats. 2342 66

Chagas disease is a neglected tropical disease and a leading cause of heart failure in Latin America caused by a protozoan called Trypanosoma cruzi. This parasite presents a complex multi-stage life cycle. Anti-Chagas drugs currently available are limited to benznidazole and nifurtimox, both with severe side effects. Thus, there is a need for alternative and more efficient drugs. Genome-scale metabolic models (GEMs) can accurately predict metabolic capabilities and aid in drug discovery in metabolic genes. This work developed an extended GEM, hereafter referred to as iIS312, of the published and validated T. cruzi core metabolism model. From iIS312, we then built three stage-specific models through transcriptomics data integration, and showed that epimastigotes present the most active metabolism among the stages (see S1-S4 GEMs). Stage-specific models predicted significant metabolic differences among stages, including variations in flux distribution in core metabolism. Moreover, the gene essentiality predictions suggest potential drug targets, among which some have been previously proven lethal, including glutamate dehydrogenase, glucokinase and hexokinase. To validate the models, we measured the activity of enzymes in the core metabolism of the parasite at different stages, and showed the results were consistent with model predictions. Our results represent a potential step forward towards the improvement of Chagas disease treatment. To our knowledge, these stage-specific models are the first GEMs built for the stages Amastigote and Trypomastigote. This work is also the first to present an in silico GEM comparison among different stages in the T. cruzi life cycle.
 ...
PMID:Genome-scale metabolic models highlight stage-specific differences in essential metabolic pathways in Trypanosoma cruzi. 3302 77