Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0151744 (myocardial ischemia)
 31,282 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Extracellular levels of amino acids in the myocardial interstitium are sensitive indicators of myocyte function. Lowered ATP leads to a rapid extracellular appearance of amino acids with a high intra- to extracellular concentration ratio, such as taurine and glutamate. Nitrogen fluxes are reflected by glutamine, while alanine, glycine, serine and leucine are markers of proteolysis. In addition, degradation of membrane phospholipids is reflected by other primary amines, such as phosphoethanolamine. The time course of these changes was determined before, during and after cardioplegic heart arrest. Two regions of the heart were monitored in 20 patients by means of microdialysis sampling. After only 20 min of heart arrest, extracellular taurine, glutamate and phosphoethanolamine increased transiently up to 25 times the basal level. Ten-20 min later, glutamine increased by 6 times. A doubling of alanine, glycine, serine and leucine levels took place 30 min after release of the aortic cross-clamp. After 2 h, all were at levels similar to those recorded 15-30 h later. Levels of taurine and glutamate in the anterior wall of the heart correlated significantly with those of its lateral wall. The response to surgery and heart arrest was studied in a group of patients with ischemic heart disease as well as in another group of patients, who underwent heart surgery for nonischemic reasons. The response of taurine and glutamine was significantly higher for the patients with ischemic heart disease, in spite of a shorter mean time of heart arrest. No sex differences were recorded. High levels of amino acids coincided frequently with clinical events, which were suggestive of ischemia, but were also recorded in a few patients without diagnosed events. We conclude that monitoring of extracellular amino acids is valuable for evaluation and development of cardioprotective strategies.
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PMID:Extracellular amino acids as markers of myocardial ischemia during cardioplegic heart arrest. 1039 96

Myocardial ischemia and reperfusion lead to myocyte cell death, at least in part, by an apoptotic mechanism. Caspases are a conserved family of proteases that play an essential role in the execution of apoptosis; however, their potential contribution to ischemic myocardial cell death is largely unknown. To examine their role in this process, we subjected rabbits to 30 min of coronary artery occlusion followed by 3 h of reperfusion. Immunoblot analyses revealed that caspases-2, -3 and -7 were proteolytically activated during myocardial ischemia and reperfusion in vivo. In addition, the well-characterized caspase substrate poly(ADP-ribose) polymerase (PARP) was selectively cleaved into its signature apoptotic fragment in ischemic/reperfused myocardium. Systemic administration of the broad-spectrum caspase inhibitor acetyl-Tyr-Val-Ala-Asp chloromethylketone (YVAD-cmk, 4.8 mg/kg) partially blocked caspase activation and dramatically reduced the percentage of terminal dUTP deoyxynucleotidyl-transferase nick end-labeling (TUNEL)-positive myocyte nuclei in the infarct region (3.9+/-0.8%v 13.0+/-2.2% in control animals, P=0.012). Moreover, YVAD-cmk reduced myocardial infarct size by approximately 31% (31.1+/-3.3%v 45.3+/-4.9% in control animals, P=0.032). These results indicate that caspases are critical mediators of myocardial injury induced by ischemia and reperfusion in vivo, and they suggest that caspase inhibition may be therapeutically beneficial in myocardial infarction.
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PMID:Caspase inhibition reduces myocyte cell death induced by myocardial ischemia and reperfusion in vivo. 1047 54

Administration of supplemental glucose and/or insulin is postulated to improve the outcome from myocardial ischemia by increasing the heart's relative utilization of glucose as an energy substrate. To examine the degree to which circulating glucose and insulin levels actually influence myocardial substrate preference in vivo, we infused conscious, chronically catheterized rats with D-[1-(13)C]glucose and compared steady-state (13)C enrichment of plasma glucose with that of myocardial glycolytic ([3-(13)C]alanine) and oxidative ([4-(13)C]glutamate) intermediary metabolites. In fasting rats, [3-(13)C]alanine-to-[1-(13)C]glucose and [4-(13)C]glutamate-to-[3-(13)C]alanine ratios averaged 0.16 +/- 0.12 and 0.14 +/- 0.03, respectively, indicating that circulating glucose contributed 32% of myocardial glycolytic flux, whereas subsequent flux through pyruvate dehydrogenase contributed 14% of total tricarboxylic acid (TCA) cycle activity. Raising plasma glucose to 11 mmol/l, or insulin to 500 pmol/l, increased these contributions equivalently. At supraphysiological (>6,500 pmol/l) insulin levels, the plasma glucose contribution to glycolysis increased further, and addition of hyperglycemia made it the sole glycolytic substrate, yet [4-(13)C]glutamate-to-[3-(13)C]alanine ratios remained </=0.60. Thus plasma levels of glucose and insulin independently regulate the proportional contribution of exogenous glucose to myocardial glycolytic and TCA cycle flux in vivo in a dose-dependent manner. However, even at supraphysiological levels, nonglucose substrates continue to supply >/=40% of myocardial TCA cycle flux.
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PMID:Regulation of myocardial [(13)C]glucose metabolism in conscious rats. 1089 78

Branched-chain amino acids (BCAAs) are oxidative energy substrates for the heart and may exert anabolic effects on myocardial protein. The factors regulating their myocardial uptake in patients with ischemic heart disease are therefore of interest. To examine whether myocardial BCAA utilization is influenced by the circulating insulin concentration, in 10 patients with chronic ischemic heart disease, we measured transmyocardial amino acid balance during fasting and again during a 90-minute euglycemic insulin infusion (plasma insulin, 218+/-25 microU x mL(-1)) with plasma BCAA concentrations held constant by coinfusion. In the fasting state, the myocardial fractional extraction of leucine (8%), isoleucine (9%), and valine (5%) from arterial plasma was slightly greater than that of glucose (3%), while net myocardial BCAA uptake (leucine, 409+/-207 nmol x min(-1); isoleucine, 220+/-144 nmol x min(-1); valine, 407+/-326 nmol x min(-1); and total BCAA uptake, 1.0+/-0.3 micromol x min(-1)) was about 13% that of glucose (8+/-2 micromol x min(-1)). During euglycemic hyperinsulinemia, myocardial glucose uptake increased 3-fold, but there was no change in the arterial-coronary sinus balance or net myocardial uptake of any BCAA under conditions where their plasma concentrations were held constant. Instead, the myocardial uptake of each BCAA correlated positively with its concentration in arterial plasma. These results demonstrate that in patients with cardiovascular disease, myocardial utilization of BCAAs is insensitive to the circulating insulin level and is regulated instead by their availability in arterial plasma. Hyperinsulinemia reduced the magnitude of both net glutamate uptake and alanine release, suggesting a possible salutary effect on myocardial oxidative efficiency.
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PMID:Effect of hyperinsulinemia on myocardial amino acid uptake in patients with coronary artery disease. 1107 31

Patients suffering from myocardial ischemia reportedly exhibit reduced in vitro binding of exogenous Co(2+) to the N-terminal of human serum albumin (HSA). The purpose of our investigation was to simulate changes in the N-terminus of HSA that may account for these ischemia-induced modifications to the cobalt binding site. HPLC, LC-MS and (1)H NMR analyses have shown that the N-terminal region of HSA Asp-Ala-His-Lys binds the transition metals Co(2+) and Ni(2+). Synthetic peptides with the first 2-12 amino acids of the HSA sequence demonstrated that the first three amino acids, Asp-Ala-His, are essential for strong binding of cobalt. Modification of the N-terminus peptide of HSA by way of N-acetylation or the deletion of one or more amino acid resulted in no binding of cobalt. Because the degradation of the susceptible, specific transition metal binding site of HSA may account for the decreased cobalt binding observed during ischemic events, an assay that detects this reduced binding could be useful in the diagnosis of ischemia.
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PMID:Characterization of the Co(2+) and Ni(2+) binding amino-acid residues of the N-terminus of human albumin. An insight into the mechanism of a new assay for myocardial ischemia. 1112 Nov

ATP-sensitive K+ (K(ATP)) channels are abundantly expressed in the heart and may be involved in the pathogenesis of myocardial ischemia. These channels are heteromultimeric, consisting of four pore-forming subunits (Kir6.1, Kir6.2) and four sulfonylurea receptor (SUR) subunits in an octameric assembly. Conventionally, the molecular composition of K(ATP) channels in cardiomyocytes and pancreatic beta -cells is thought to include the Kir6.2 subunit and either the SUR2A or SUR1 subunits, respectively. However, Kir6.1 mRNA is abundantly expressed in the heart, suggesting that Kir6.1 and Kir6.2 subunits may co-assemble to form functional heteromeric channel complexes. Here we provide two independent lines of evidence that heteromultimerization between Kir6.1 and Kir6.2 subunits is possible in the presence of SUR2A. We generated dominant negative Kir6 subunits by mutating the GFG residues in the channel pore to a series of alanine residues. The Kir6.1-AAA pore mutant subunit suppressed both wt-Kir6.1/SUR2A and wt-Kir6.2/SUR2A currents in transfected HEK293 cells. Similarly, the dominant negative action of Kir6.2-AAA does not discriminate between either of the wild-type subunits, suggesting an interaction between Kir6.1 and Kir6.2 subunits within the same channel complex. Biochemical data support this concept: immunoprecipitation with Kir6.1 antibodies also co-precipitates Kir6.2 subunits and conversely, immunoprecipitation with Kir6.2 antibodies co-precipitates Kir6.1 subunits. Collectively, our data provide direct electrophysiological and biochemical evidence for heteromultimeric assembly between Kir6.1 and Kir6.2. This paradigm has profound implications for understanding the properties of native K(ATP)channels in the heart and other tissues.
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PMID:Is the molecular composition of K(ATP) channels more complex than originally thought? 1144 41

Myocardial ischaemia and reperfusion lead to myocardial cell death due, at least in part, to apoptotic mechanisms. Although cysteinyl aspartate-specific proteinase (caspase) activation is a major event and the most-cited culprit in the development of apoptosis, its potential contribution to ischaemic myocardial cell death is largely unknown. To study the role of caspase activation, isolated rat hearts (n=6 per group) were subjected to 30 min coronary artery occlusion followed by 120 min reperfusion. A non-selective [0.1 or 0.5 microM acetyl-Tyr-Val-Ala-Asp chloromethylketone (YVAD-cmk)] or selective caspase inhibitors [0.07 or 0.2 microM acetyl-Asp-Glu-Val-Asp-cmk (Ac-DEVD-cmk, caspase-3 inhibitor); 0.07 or 0.2 microM benzoxycarbonyl-Leu-Glu-OMe-His-Asp(OMe)-fluoromethylketone (z-LEHD-fmk, caspase-9 inhibitor)] were added to the perfusate at the start of reperfusion. Non-selective caspase inhibition with 0.1 or 0.5 microM YVAD-cmk limited infarct size: (21 +/- 4%, P<0.05; 17 +/- 3%, P<0.05, respectively) compared with the ischaemic/reperfused control (32 +/- 5%). In hearts treated with 0.1 or 0.5 microM caspase II non-selective inhibitor, the fraction of terminal-deoxynucleotidyl-transferase deoxyuridine nick end labelling (TUNEL)-positive myocyte nuclei in the infarcted zone was reduced from the ischaemic/reperfused non-treated control of 11.2 +/- 2.1% to 6.2 +/- 1.6% (P<0.05) and 1.2 +/- 0.2% (P<0.05), respectively. The recovery of post-ischaemic cardiac function (coronary flow, aortic flow and left-ventricular developed pressure) improved significantly with the application of the non-selective caspase inhibitor as well. In hearts perfused with specific caspase inhibitors (caspase-3 and caspase-9) there was no significant reduction in the infarct size, no improvement in post-ischaemic cardiac function and no reduction of apoptotic cell death. We conclude that non-specific inhibition of caspases may be therapeutically beneficial in myocardial ischaemia/reperfusion-induced damage, while selective caspase inhibitors may fail to prevent such reperfusion-induced injury in our model system.
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PMID:Non-specific caspase inhibition reduces infarct size and improves post-ischaemic recovery in isolated ischaemic/reperfused rat hearts. 1177 4

Endogenous glycogen stores are essential to maintain cell functions during myocardial ischemia.. Fasting and L-glutamate improve left ventricular function after an ischemic episode. We studied their effects on myocardial glycogen depletion during ischemia and on left ventricular function and glycogen resynthesis during reperfusion. We allocated 185 Wistar rats to 4 groups: 1) Control, 2) Fasting, 16-20 hours (Fast) 3) L-glutamate supplementation [100 mM] (Glt) or 4) Fasting + L-glutamate supplementation [100 mM]. n = 8-10 in each group. Hearts were mounted in an isolated perfused rat hearts model for 20 min stabilisation, 10/20/30 min ischemia and 60 min reperfusion. At each time point hearts were frozen in liquid nitrogen (-196 degrees C) within 2 seconds and myocardial contents of glycogen, lactate, alanine and glutamate were determined. Left ventricular pressure was measured continuously. Fasting and L-glutamate supplementation improved LV function after ischemia (Fast: p < 0.05, Glt: p < 0.01) and delayed myocardial glycogen depletion (Fast: p < 0.05, Glt: p < 0.01) compared to control. Decreased lactate accumulation and increased alanine content during ischemia were found in fasted (lactate: p < 0.05, alanine: p < 0.05) and L-glutamate supplemented (lactate: p < 0.01, alanine: p < 0.01) hearts compared to control. We did not find any additive effects of fasting and L-glutamate supplementation. In conclusion fasting and L-glutamate supplementation improve left ventricular function during reperfusion and delay myocardial glycogen depletion during ischemia. There were no additive effects of Fasting and L-glutamate supplementation. These finding suggest common metabolic pathways underlying the effects of L-glutamate supplementation and fasting.
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PMID:Effects of L-glutamate supplementation mimic effects of fasting in the ischemic heart. 1287 62

PKC-delta is believed to play an essential role in cardiomyocyte growth. In the present study, we investigated the effect of PKC-delta on cardiac metabolism using PKC-delta knockout mice generated in our laboratories. Proteomic analysis of heart protein extracts revealed profound changes in enzymes related to energy metabolism: certain isoforms of glycolytic enzymes, e.g., lactate dehydrogenase and pyruvate kinase, were absent or decreased, whereas several enzymes involved in lipid metabolism, e.g., phosphorylated isoforms of acyl-CoA dehydrogenases, showed a marked increase in PKC-delta(-/-) hearts. Moreover, PKC-delta deficiency was associated with changes in antioxidants, namely, 1-Cys peroxiredoxin and selenium-binding protein 1, and posttranslational modifications of chaperones involved in cytoskeleton regulation, such as heat shock protein (HSP)20, HSP27, and the zeta-subunit of the cytosolic chaperone containing the T-complex polypeptide 1. High-resolution NMR analysis of cardiac metabolites confirmed a significant decrease in the ratio of glycolytic end products (alanine + lactate) to end products of lipid metabolism (acetate) in PKC-delta(-/-) hearts. Taken together, our data demonstrate that loss of PKC-delta causes a shift from glucose to lipid metabolism in murine hearts, and we provide a detailed description of the enzymatic changes on a proteomic level. The consequences of these metabolic alterations on sensitivity to myocardial ischemia are further explored in the accompanyingpaper (20).
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PMID:Loss of PKC-delta alters cardiac metabolism. 1527 8

Acute and chronic ischaemic diseases are among the main death reasons and civilized world menace. Branched chain amino acids (BCAAs): valine (Val), leucine (Leu), and isoleucine (Ile) are the main source of nitrogen to glutamine (Gln) and alanine (Ala) synthesis in muscles. In numerous cachexy-producing illnesses such as cancer, sepsis, diverse injuries and heart diseases increased consumption of BCAAs occurs. In myocardial ischemia BCAAs derived from the mobilization of muscle protein may be an important alternative energy substrate for the heart. BCAAs are oxidative energy substrates for the heart and may exert anabolic effects on myocardial protein (8). The aim of our study was to determine branched chain amino acids (BCAAs) concentrations in blood plasma of patients with chronic and acute ischeamic heart disease and to find out changes that those amino acids undergo during the first five days of patients' hospitalization.
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PMID:Branched chain amino acids (BCAAs) in heart diseases (ischaemic heart disease and myocardial infarction). 1614 56


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