Elevated levels of protein phosphatase 1 and phosphatase 2A may contribute to cardiac dysfunction in diabetes

AbstractAlthough protein phosphorylation and dephosphorylation are known to regulate the activities of different enzymes, sufficient information on the role of dephosphorylation in cardiac function is not available. Since protein phosphatases mediate dephosphorylation, it is possible that cardiac dysfunction induced by diabetes may be due to alterations in the activities of these enzymes. We therefore determined cardiac protein phosphatase activity as well as protein contents of phosphatase 1 and phosphatase 2A in diabetic animals. For this purpose, rats were made diabetic by administering a single intravenous injection of streptozotocin (65 mg/kg body weight) and hearts were examined after 1, 2, 3, 4 and 8 weeks. Some of the 4-week diabetic animals received subcutaneous injections of insulin (3 U/day) for a further period of 4 weeks. Cardiac dysfunction was evident after 2 weeks of inducing diabetes and deteriorated further with time. A significant increase in protein phosphatase activity appeared after 1 week and persisted until 8 weeks. Increased protein phosphatase activity in the diabetic heart was associated with a corresponding increase in the protein contents of both phosphatase 1 and phosphatase 2A. Insulin treatment partly prevented the changes observed in diabetic animals. The results suggest that increased protein phosphatase activities and subsequent enhanced protein dephosphorylation may play a role in diabetes-induced cardiac dysfunction

Carbon Dioxide Water-bath Treatment Augments Peripheral Blood Flow through the Development of Angiogenesis

In this study, we investigated the effects of CO2 water-bath therapy on blood flow and angiogenesis in the ischemic hind limb as well as some plasma angiogenic factors in peripheral ischemic model. The hind limb ischemia was induced by occluding the femoral artery for 2 weeks in rats and treated with or without CO2 water-bath therapy at 37째C for 4 weeks (20 min treatment everyday for 5 days per week). The peak blood flow as well as minimal and mean blood flow in the ischemic skeletal muscle were markedly increased by the CO2 water-bath therapy. This increase in blood flow was associated with development of angiogenesis in the muscle as well as reduction in the ischemia-induced increase in plasma malondialdehyde levels. Although plasma vascular endothelial growth factor and nitric oxide levels were increased in animals with peripheral ischemia, the changes in these biomarkers were not affected by CO2 water-bath therapy. These results suggest that augmentation of blood flow in the ischemic hind limb by CO2 water-bath therapy may be due to the development of angiogenesis and reduction in oxidative stress.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Modification of ischemia/reperfusion induced infarct size by ischemic preconditioning in hypertrophied hearts

This study examined the effects of ischemic preconditioning (IP) on the ischemia/reperfusion (I/R) induced injury in normal and hypertrophied hearts. Cardiac hypertrophy in rabbits was induced by L-thyroxine (0.5 mg/kg/day for 16 days). Hearts with or without IP (3 cycles of 5 min ischemia and 10 min reperfusion) were subjected to I/R (60 min ischemia followed by 60 min reperfusion). IP reduced the I/R-induced infarct size from 68% to 24% and 57% to 33% in the normal and hypertrophied hearts, respectively. Leakage of creatine phosphokinase in the perfusate from the hypertrophied hearts due to I/R was markedly less than that form the normal hearts; IP prevented these changes. Although IP augmented the increase in phosphorylated p38-mitogen-activated protein kinase (p38-MAPK) content due to I/R, this effect was less in the hypertrophied than in the normal heart. These results suggest that reduced cardioprotection by IP of the I/R-induced injury in hypertrophied hearts may be due to reduced activation of p38-MAPK in comparison with normal hearts.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Both β-1 adrenoceptors and AT1 receptors may not be involved in the catecholamine-induced lethal arrhythmias

Although an excessive amount of catecholamines is known to produce arrhythmias, the exact mechanisms of this derangement are not fully understood. For this purpose, Sprague-Dawley rats were treated with or without atenolol, a -adrenoceptor blocker (20 mg/kg/day), for 15 days followed by injections of epinephrine for cumulative doses of 4 to128 µg/kg. Another group of animals was pretreated with losartan, an angiotensin receptor (AT1) blocker (20 mg/kg/day) for comparison. Varying degrees of ventricular arrhythmias were seen upon increasing the dose of epinephrine but the incidence or the duration of rhythm abnormalities as well as number of episodes and severity of arrhythmias were not affected upon treating the animals with atenolol or losartan. The levels of both epinephrine and norepinephrine were increased in the atenolol-treated rats but unchanged in the losartan-treated animals after the last injection of epinephrine; the severity of arrhythmias did not correlate with the circulating catecholamine levels. These results indicate that both -adrenoceptors and AT1 receptors may not be involved in the pathogenesis of catecholamine-induced arrhythmias and support the view that other mechanisms such as oxidation products of catecholamines may play a crucial role in the occurrence of lethal arrhythmias.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Involvement of Oxidative Stress in the Development of Subcellular Defects and Heart Disease

It is now well known that oxidative stress promotes lipid peroxidation, protein oxidation, activation of proteases, fragmentation of DNA and alteration in gene expression for producing myocardial cell damage, whereas its actions for the induction of fibrosis, necrosis and apoptosis are considered to result in the loss of cardiomyocytes in different types of heart disease. The present article is focused on the discussion concerning the generation and implications of oxidative stress from various sources such as defective mitochondrial electron transport and enzymatic reactions mainly due to the activation of NADPH oxidase, nitric oxide synthase and monoamine oxidase in diseased myocardium. Oxidative stress has been reported to promote excessive entry of Ca2+ due to increased permeability of the sarcolemmal membrane as well as depressions of Na+-K+ ATPase and Na+-Ca2+ exchange systems, which are considered to increase the intracellular of Ca2+. In addition, marked changes in the ryanodine receptors and Ca2+-pump ATPase have been shown to cause Ca2+-release and depress Ca2+ accumulation in the sarcoplasmic reticulum as a consequence of oxidative stress. Such alterations in sarcolemma and sarcoplasmic reticulum are considered to cause Ca2+-handling abnormalities, which are associated with mitochondrial Ca2+-overload and loss of myofibrillar Ca2+-sensitivity due to oxidative stress. Information regarding the direct effects of different oxyradicals and oxidants on subcellular organelles has also been outlined to show the mechanisms by which oxidative stress may induce Ca2+-handling abnormalities. These observations support the view that oxidative stress plays an important role in the genesis of subcellular defects and cardiac dysfunction in heart disease

Effects of CO2 water-bath treatment on blood flow and angiogenesis in ischemic hind limb of diabetic rat

The effects of CO2 water-bath therapy in the hind limb of diabetic animals with or without peripheral ischemia were examined. Diabetes was induced in rats by streptozotocin (65 mg/kg) and the animals were divided into three groups. After 4 weeks, peripheral ischemia was induced by ligation of the femoral artery for 2 weeks in two groups (Diabetic Ischemic) of diabetic rats, whereas the femoral artery was not occluded in the third group (Diabetic). All these animals were subjected to water-bath therapy (with or without CO2 mixing; 20 min per day for 5 days per week) for a period of 4 weeks. Both peak and mean flows, unlike minimal flow, in diabetic ischemic limbs were increased by about 2 fold by CO2 bath treatment. Morphological examination of hind limb tissue sections revealed about 2 fold increase in the small artery count in diabetic ischemic animals upon CO2 bath treatment. These results indicate that CO2 water-bath therapy augments the blood flow and development of angiogenesis in the skeletal muscle of diabetic ischemic animals and thus may be of some benefits for the treatment of peripheral arterial disease in diabetes.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author