Selenium improves cardiac function by attenuating the activation of NF-kappaB due to ischemia-reperfusion injury

Although selenium, an essential trace element and a component of glutathione peroxidase, is known to protect the heart from ischemia-reperfusion (I/R)-induced injury, the mechanisms of this protection are not fully understood. For this purpose, isolated rat hearts were subjected to 30 min of global ischemia followed by 30 min of reperfusion; sodium selenite (25-1,000 nM) was added in the perfusion medium 10 min prior to ischemia, as well as during reperfusion. Selenium caused a dose-dependent improvement in cardiac performance and attenuated the decrease in the ratio of reduced glutathione to oxidized glutathione, as well as the increased level of malondialdehyde in I/R heart. Elevated ratios of nuclear factor-kappaB (NF-kappaB) in particulate and cytosolic fraction and of phosphorylated NF-kappaB and total NF-kappaB in I/R hearts were reduced by selenium. Cardiac dysfunction in hearts perfused with xanthine plus xanthine oxidase mixture, as well as hydrogen peroxide, or subjected to Ca2+ paradox was also attenuated by selenium. These data suggest that selenium protects the heart against I/R injury due to its action on the redox state and deactivation of NF-kappaB in I/R hearts.     

Sarcolemmal Na+-K+-ATPase activity in diabetic rat heart

Heart sarcolemmal membranes were isolated by the hypotonic shock-LiBr treatment from rats with chronic diabetes induced by a streptozotocin (65 mg/kg, iv) injection. Sarcolemmal Mg2+-dependent ATPase activity was elevated, whereas 5'-nucleotidase and K+-p-nitrophenylphosphatase activities in diabetic heart were depressed in comparison to control preparations. Although patent Na+-K+-ATPase and patent ouabain-sensitive Na+-K+-ATPase activities were unaltered, latent Na+-K+-ATPase activities, as determined in membranes after alamethicin or deoxycholate treatments, were found to be significantly depressed in diabetic animals. A depression in the latent Na+-K+-ATPase activity in diabetic preparations was also observed in membranes prepared by the sucrose density gradient method. Insulin-treated diabetic rats were observed to have normalized latent Na+-K+-ATPase activities. Total phospholipid content did not differ, but cholesterol content of the sarcolemmal membranes was significantly increased in diabetic heart preparations. Sarcolemmal Na+-K+-ATPase activity in diabetic heart was more resistant to treatments with filipin, an agent known to bind with cholesterol residues. These results suggest that chronic experimental diabetes is associated with some defects in sarcolemmal enzymatic activities and composition.     

Possible role of sarcolemmal Ca2+/Mg2+ ATPase in heart function

The Ca2+/Mg2+ ATPase, which is activated by millimolar concentrations of Ca2+ or Mg2+, has been found to exist in the heart sarcolemmal membrane. Although a great deal of work has been carried out to characterize the enzyme activity as well as to purify the enzyme, the physiological function of the enzyme remains to be elucidated. This enzyme has been shown to be different from other known ion transport ATPases such as Na(+)-K+ ATPase and Ca2(+)-stimulated ATPase in terms of the activation kinetics of various cations, the sensitivity towards specific inhibitors, and the molecular weights. In view of the existing data and circumstantial evidence, it has been proposed that the Ca2+/Mg2+ ATPase is involved in the entry of Ca2+ into the cardiac cells, the transport of Mg2+ across the cell membrane, and extracellular ATP signal transduction.     

Carnitine Palmitoyltransferase-I,a New Target for the Treatment of Heart Failure

Although the heart is capable of extracting energy from different types of substrates such as fatty acids and carbohydrates, fatty acids are the preferred fuel under physiological conditions. In view of the presence of diverse defects in myocardial metabolism in the failing heart, changes in metabolism of glucose and fatty acids are considered as viable targets for therapeutic modification in the treatment of heart failure. One of these changes involves the carnitine palmitoyltransferase (CPT) enzymes, which are required for the transfer of long chain fatty acids into the mitochondrial matrix for oxidation. Since CPT inhibitors have been shown to prevent the undesirable effects induced by mechanical overload, e.g. cardiac hypertrophy and heart failure, it was considered of interest to examine whether the inhibition of CPT enzymes represents a novel approach for the treatment of heart disease. A shift from fatty acid metabolism to glucose metabolism due to CPT-I inhibition has been reported to exert beneficial effects in both cardiac hypertrophy and heart failure. Since the inhibition of fatty acid oxidation is effective in controlling abnormalities in diabetes mellitus, CPT-I inhibitors may also prove useful in the treatment of diabetic cardiomyopathy. Accordingly, it is suggested that CPT-I may be a potential target for drug development for the therapy of heart disease in general and heart failure in particular.     

Cardiac myofibrillar ATPase activity in diabetic rats

Diabetes was induced by an intravenous injection of 65 mg/kg streptozotocin and hearts were removed 8 weeks later for the isolation of myofibrils. The basal ATPase activity of myofibrils from diabetic hearts was significantly lower than the controls. Although Ca²⁺-stimulated ATPase activity was also depressed in diabetic myocardium, the dependency of diabetic myofibrils on free calcium concentration was not different from that of control. The basal and Ca²⁺-stimulated ATPase activities in diabetic rats demonstrated a greater sensitivity to KCl than control preparations. The myofibrillar basal ATPase, unlike Ca²⁺-stimulated ATPase, in diabetic animals exhibited a greater sensitivity to ethylene glycol. These results support the view regarding the presence of some subtle structural and conformational changes in diabetic myofibrils.