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ABSTRACT: This study was undertaken to examine the effects of dietary supplementation of cysteine and taurine in rats with diabetes induced with streptozotocin (STZ, 65 mg/kg body weight). Experimental animals were treated orally (by gavage) with cysteine (200 mg/kg) and taurine (400 mg/kg), alone or in combination, daily for 8 wks. In one group, rats were also pretreated 3 wks before the induction of diabetes (prevention arm) whereas in the other, the treatment was started 3 days after the induction of diabetes (reversal arm). Diabetes increased heart weight/body weight (HW/BW) ratio, plasma glucose, triglyceride and cholesterol levels as well as depressed heart rate (HR), blood pressure, left ventricular systolic pressure (LVSP), rate of contraction (+dP/dt), rate of relaxation (-dP/dt), fractional shortening (FS) and cardiac output (CO). The left ventricular internal diameter in systole (LViDs) was increased whereas that in diastole (LViDd) was decreased. In the prevention arm, treatment of the diabetic animals with cysteine or taurine decreased HW/BW ratio and improved HR, FS, +dP/dt and -dP/dt, as well as normalized LViDs, without altering the increase in glucose level. Cysteine decreased plasma triglyceride and cholesterol levels and improved LVSP whereas CO was improved by taurine. In the reversal arm, cysteine alone or with taurine did not correct the changes in hemodynamic parameters, FS and plasma triglycerides. Diabetes-induced cardiac dysfunction and increases in plasma triglycerides can be prevented, but not reversed, by dietary cysteine alone or in combination with taurine.
Physiological research / Academia Scientiarum Bohemoslovaca 12/2012; · 1.55 Impact Factor
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ABSTRACT: The accumulation of lipids within arteries remains to be the initial impulse for the pathogenesis of atherosclerosis; however, both inflammation and oxidative stress are considered to play a critical role in this process. Several lipid lowering drugs are used as the first line therapy in atherosclerosis; however, different agents have been found to exhibit beneficial effects which are independent of their lipid lowering activity. Both statins and fibrates have been reported to exert anti-inflammatory and anti-oxidative effects in addition to their anti-atherosclerotic actions. Furthermore, anti-hypertensive, anti-diabetic and anti-platelet drugs, which reduce oxidative stress and inflammation, have been shown to attenuate atherosclerosis. In addition, novel substances such as HDL-related agents, cyclopentenone prostaglandins, lipoprotein-associated phospholipase A(2) inhibitors, 5-lipoxygenase pathway inhibitors, acyl CoA: cholesterol acyltransferase inhibitors, analogues of probucol and lysophosphatidic acid antagonists have been developed for the treatment of atherosclerosis as a consequence of their actions on oxidative stress and inflammation. The present article reviews the involvement of inflammation and oxidative stress in the pathogenesis of atherosclerosis and focuses on the mechanisms of some clinically used as well as potential anti-atherosclerotic substances with anti-inflammatory and anti-oxidative properties.
Current pharmaceutical design 01/2009; 15(27):3094-107. · 4.41 Impact Factor
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ABSTRACT: Post-myocardial infarction (MI) remodeling of cardiac myocytes and the myocardial interstitium results in alteration of gross ventricular geometry and ventricular dysfunction. To investigate the mechanisms of the remodeling process of the heart after large MI, the expression of various genes in viable left ventricle and infarct scar tissue were examined at 16 weeks post-MI. Steady-state expression of Na+-K+ATPase -1 and −2, phospholamban (PLB), -myosin heavy chain (-MHC), ryanodine receptor (Rya) and Ca2+ ATPase (Serca2) mRNAs were decreased in the infarct scar vs noninfarcted sham-operated controls (P < 0.05). On the other hand, Gi2 and β-MHC mRNAs were upregulated (P < 0.05, respectively) in the infarct scar whereas Na+-K+ ATPase-β, Na+-Ca2+ exchanger and Gs mRNAs were not altered vs control values. In viable left ventricle, the a-1 subunit of Na+-K+ATPase, -3, β-isoforms, Rya, β-MHC, Gi2, Gs and Na+-Ca2+ exchanger were significantly elevated while expression of the a-2 subunit of Na+-K+ ATPase, PLB and Serca2 were significantly decreased compared to controls. Expression of CK2 mRNA was elevated in noninfarcted heart (145 ± 15%) and diminished in the infarct scar (66 ± 13%) vs controls. Expression of β-MHC mRNA was elevated in both viable and infarct scar tissues of experimental hearts (140 ± 31% and 183 ± 30% vs. controls, respectively). These results suggest that cardiac genes in the infarcted tissue and viable left ventricle following MI are differentially regulated.
Journal of Cellular and Molecular Medicine 12/2003; 8(1):85 - 92. · 4.13 Impact Factor
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ABSTRACT: Although ischemia reperfusion has been shown to depress gene expression of the sarcoplasmic reticulum (SR) proteins, such as the ryanodine receptor, Ca2+-pump ATPase, phospholamban, and calsequestrin in the heart, the mechanisms of these changes are not understood. Given the occurrence of hypoxia and the lack of glucose during the ischemic phase, we investigated the effects of these factors on the cardiac SR gene expression. Isolated rat hearts perfused in the absence of oxygen and/or glucose for 30 min showed an increase in the expression of SR genes. However, perfusion of hearts for 60 min with normal oxygenated medium after 30 min of lack of both oxygen and glucose depressed the transcript levels for the SR proteins; these changes did not occur when hearts were deprived of either oxygen or glucose. The effect of intracellular Ca2+-overload, which occurs during reperfusion, was studied by using hearts perfused for 5 min with Ca2+-free medium and then reperfused for 30 min. Ca2+-depletion/repletion induced a dramatic decrease in the transcript levels of the SR genes. These results suggest that the lack of both oxygen and glucose during ischemia are necessary for reperfusion-induced depression in SR gene expression, possibly due to the occurrence of intracellular Ca2+-overload.
The FASEB Journal 12/2001; 15(13):2515-7. · 5.71 Impact Factor
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ABSTRACT: In view of the depressed sarcoplasmic reticulum (SR) Ca2+-pump and Ca2+-release activities in the diabetic heart and the critical role of phosphorylation in regulating the SR function, we examined the status of Ca2+-calmodulin-dependent protein kinase (CaMK) and cAMP-dependent protein kinase (PKA)-mediated phosphorylations in the diabetic heart. Diabetes was induced in male Sprague-Dawley rats by an injection of streptozotocin (65 mg/kg i.v.), and the animals were killed 6 weeks later for assessment of the ventricular SR function. Depressed cardiac performance and SR Ca2+-uptake and -release activities in diabetic animals were accompanied by a significant decrease in the level of SR Ca2+-cycling proteins, such as ryanodine receptor, Ca2+-pump ATPase, and phospholamban. On the other hand, the CaMK- and PKA-mediated phosphorylations of these Ca2+-cycling proteins, the endogenous SR CaMK and PKA activities, and the endogenous SR and cytosolic phosphatase activities were increased in the diabetic heart. Treatment of 3-week diabetic animals with insulin partially or fully prevented the diabetes-induced changes in cardiac performance, SR Ca2+-uptake and -release activites, and SR protein content, whereas the diabetes-induced changes in SR CaMK- and PKA-mediated phosphorylations and activities, as well as phosphatase activities, were not significantly affected. These results suggest that the reduced content of the Ca2+-cycling proteins, unlike alterations in PKA and phosphatase activities, appear to be the major defect underlying SR dysfunction in the diabetic heart.
Diabetes 10/2001; 50(9):2133-8. · 8.29 Impact Factor
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ABSTRACT: Although the involvement of serotonin in exacerbating vascular abnormalities in ischemic heart disease has been established, its role in mediating changes in cardiac function due to ischemia reperfusion (IR) is poorly understood. The aim of this study was to investigate the effect of a serotonin blocker, sarpogrelate (5-HT2A antagonist), in preventing cardiac injury due to IR. Isolated rat hearts were subjected to 30 min of global ischemia followed by 1 h of reperfusion. Sarpogrelate (50 nM-0.9 microM) was infused 10 min before ischemia as well as during the reperfusion period. The IR-induced changes in left ventricular developed pressure, left ventricular end diastolic pressure, rate of pressure development, and rate of pressure decay were attenuated (P < 0.05) with sarpogrelate treatment. Sarpogrelate also decreased the ultrastructural damage and improved the high energy phosphate level in the IR hearts (P < 0.05). This study provides evidence for the attenuation of IR-induced cardiac injury by 5-HT2A receptor blockade and supports the view that serotonin may contribute to the deleterious effects of IR in the heart.
Canadian Journal of Physiology and Pharmacology 09/2001; 79(9):761-7. · 1.95 Impact Factor
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ABSTRACT: Serotonin can induce proliferation of vascular smooth muscle cells. We assessed the ability of a specific serotonin receptor antagonist, sarpogrelate, to inhibit proliferation of cultured porcine coronary artery smooth muscle cells.
Cell proliferation and mitotic activity were measured using 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide. To determine the effect of sarpogrelate on DNA (deoxyribonucleic acid), RNA (ribonucleic acid), and protein synthesis, radioactive incorporation of 3H-thymidine, 3H-uridine, and 3H-phenylalanine, respectively, was used. Synthesis of DNA was also assessed by flow cytometry with propidium iodide as a fluorochrome.
Serotonin, platelet-derived growth factor, endothelin, and angiotensin II all induced proliferation of porcine coronary artery smooth muscle cells. Sarpogrelate specifically inhibited the serotonin-induced cytokine trigger but did not influence platelet-derived growth factor-, endothelin-, or angiotensin II-induced cell proliferation. Sarpogrelate inhibited the serotonin-induced increase in intracellular free ionized calcium concentration, prevented mitogen-activated protein kinase activation, and down-regulated expression of the protooncogenes c-fos and c-jun. Sarpogrelate acted at the G1 phase of the cell cycle.
These data suggest that sarpogrelate could be used as a therapeutic agent to inhibit serotonin-induced neointimal hyperplasia and improve patency of coronary artery bypass grafts.
The Annals of Thoracic Surgery 07/2001; 71(6):1856-64; discussion 1865. · 3.74 Impact Factor
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ABSTRACT: Evidence indicates that, in addition to the L-type Ca2+ channel blockade, Ca2+-antagonists target other functions including the Ca2+-pumps. This study was conducted to test the possibility that the reported inhibition of heart sarcolemmal (SL) and sarcoplasmic reticular (SR) Ca2+-pumps by verapamil and diltiazem could be due to drug-induced depression of phosphatidylethanolamine (PE) N-methylation which modulates these Ca2+-transport systems. Three catalytic sites individually responsible for the synthesis of PE monomethyl (site I), dimethyl (site II) and trimethyl (phosphatidylcholine (PC), site III) derivates were examined in SL and SR membranes by employing different concentrations of S-adenosyl-L-methionine (AdoMet). Total methyl group incorporation into SL PE, in vitro, was significantly depressed by 10(-6)-10(-3) M verapamil or diltiazem at site III. The catalytic activity of site I was inhibited by 10(-3) M verapamil only, whereas the site II activity was not affected by these drugs. The inhibition induced by verapamil or diltiazem (10(-5) M) was associated with a depression of the Vmax value without any change in the apparent affinity for AdoMet. Both drugs decreased the SR as well as mitochondrial PE N-methylation at site III. A selective depression of site III activity was also observed in SL isolated from hearts of rats treated with verapamil in vivo. Furthermore, administration of [3H-methyl]-methionine following the treatment of animals with verapamil, reduced the synthesis of PC by N-methyltransferase. Verapamil also depressed the N-methylation-dependent positive inotropic effect induced by methionine in the isolated Langendorff heart. Both agents depressed the SL Ca2+-pump and although diltiazem also inhibited the SR Ca2+-pump, verapamil exerted a stimulatory effect. In addition, verapamil decreased SR Ca2+-release. These results suggest that verapamil and diltiazem alter the cardiac PE N-methyltransferase system. This action is apparently additional to the drugs' effect on L-type Ca2+ channels and may serve as a biochemical mechanism for the drugs' inhibition of the cardiac Ca2+-pumps and altered cardiac function.
Molecular and Cellular Biochemistry 06/2001; 221(1-2):89-98. · 2.06 Impact Factor
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ABSTRACT: The sarcoplasmic reticulum (SR) is a major player in maintaining cardiac function, as it is intimately involved in the regulation of Ca2+-movements on a beat-to-beat basis. SR dysfunction due to abnormalities in SR protein content has been reported in different cardiac diseases such as ischaemic heart disease, myocardial infarction, congestive heart failure and various cardiomyopathies; thus the genes expressing the SR Ca2+-pump, Ca2+-channels, calsequestrin, phospholamban and other regulatory proteins are considered important targets for drug development. In our experience, ischaemic preconditioning (IP) and pharmacological therapies, such as anti-oxidants, beta-adrenergic receptor blockers, angiotensin receptor (AT-1) blockers, angiotensin converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers are effective therapies that improve cardiac performance in the failing heart by improving SR function. Accordingly, this paper is intended to shed light on the knowledge in the field of cardiac therapy targeted to improve and protect SR function.
Expert opinion on therapeutic targets 05/2001; 5(2):205-17. · 3.72 Impact Factor
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ABSTRACT: Although an excessive amount of circulating catecholamines is known to induce cardiomyopathy, the mechanisms are poorly understood. This study was undertaken to investigate the role of oxidative stress in catecholamine-induced heart dysfunction. Treatment of rats for 24 h with a high dose (40 mg/kg) of a synthetic catecholamine, isoproterenol, resulted in increased left ventricular end diastolic pressure, depressed rates of pressure development, and pressure decay as well as increased myocardial Ca2+ content. The increased malondialdehyde content, as well as increased formation of conjugated dienes and low glutathione redox ratio were also observed in hearts from animals injected with isoproterenol. Furthermore, depressed cardiac sarcolemmal (SL) ATP-dependent Ca2+ uptake, Ca2+-stimulated ATPase activity, and Na+-dependent Ca2+ accumulation were detected in experimental hearts. All these catecholamine-induced changes in the heart were attenuated by pretreatment of animals with vitamin E, a well-known antioxidant (25 mg/kg/day for 2 days). Depressed cardiac performance, increased myocardial Ca2+ content, and decreased SL ATP-dependent, and Na+-dependent Ca2+ uptake activities were also seen in the isolated rat hearts perfused with adrenochrome, a catecholamine oxidation product (10 to 25 microg/ml). Incubation of SL membrane with different concentrations of adrenochrome also decreased the ATP-dependent and Na+-dependent Ca2+ uptake activities. These findings suggest the occurrence of oxidative stress, which may depress the SL Ca2+ transport and result in the development intracellular Ca2+ overload and heart dysfunction in catecholamine-induced cardiomyopathy.
Archives of Biochemistry and Biophysics 04/2001; 387(1):85-92. · 2.93 Impact Factor
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ABSTRACT: The cardiac sarcolemmal membrane cis -unsaturated fatty acid-sensitive phospholipase D hydrolyzes phosphatidylcholine to form phosphatidic acid. The functional significance of phosphatidic acid is indicated by its ability to increase [Ca(2+)](i)and augment cardiac contractile performance via the activation of phospholipase C. Accordingly, we tested the hypothesis that a defect occurs in the membrane level of phosphatidic acid and/or the responsiveness of cardiomyocytes to phosphatidic acid in congestive heart failure due to myocardial infarction. Myocardial infarction was produced in rats by ligation of the left coronary artery while sham-operated animals served as control. At 8 weeks after surgery, the experimental animals were at a stage of moderate congestive heart failure. Compared to sham controls, phosphatidic acid-mediated increase in [Ca(2+)](i), as determined by the fura 2-AM technique, was significantly reduced in failing cardiomyocytes. Immunoprecipitation of sarcolemmal phospholipase C isoenzymes using specific monoclonal antibodies revealed that the stimulation of phospholipase C gamma(1)and delta(1)phosphatidylinositol 4,5-bisphosphate hydrolyzing activities by phosphatidic acid was decreased in the failing heart. Although the activity of phospholipase C beta(1)in the failing heart was higher than the control, phosphatidic acid did not stimulate this isoform in control sarcolemma, and produced an inhibitory action in the failing heart preparation. Furthermore, the specific binding of phosphatidic acid to phospholipase C gamma(1)and delta(1)isoenzymes was decreased, whereas binding to phospholipase beta(1)was absent in the failing heart. A reduction in the intramembranal level of phosphatidic acid derived via cis -unsaturated fatty acid-sensitive phospholipase D was also seen in the failing heart. These findings suggest that a defect in phosphatidic acid-mediated signal pathway in sarcolemma may represent a novel mechanism of heart dysfunction in congestive heart failure.
Journal of Molecular and Cellular Cardiology 04/2001; 33(3):431-40. · 5.17 Impact Factor
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ABSTRACT: Phosphatidylinositol 4,5-bisphosphate (PtdIns 4,5-P(2)) is not only a precursor to inositol 1,4,5-trisphosphate (Ins 1,4, 5-P(3)) and sn-1,2 diacylglycerol, but also essential for the function of several membrane proteins. The aim of this study was to evaluate the changes in the level of this phospholipid in the cell plasma membrane (sarcolemma, SL) of cardiomyopathic hamster (CMPH) heart.
We examined the cardiac SL PtdIns 4,5-P(2) mass and the activities of the enzymes responsible for its synthesis and hydrolysis in 250-day-old UM-X7.1 CMPH at a severe stage of congestive heart failure (CHF) and in age-matched controls (Syrian Golden hamsters).
The SL PtdIns 4,5-P(2) mass in CMPH was reduced by 72% of the control value. The activities of PtdIns 4 kinase and PtdIns 4-P 5 kinase were depressed by 69 and 50% of control values, respectively. Although, the total phospholipase C (PLC) activity was moderately, although significantly, decreased (by 18% of control), PLCdelta(1) isoenzyme activity in the SL membrane was elevated, with a concomitant increase in its protein content, whereas PLCbeta(1) and gamma(1) isoenzyme activities were depressed despite the increase in their protein levels. A 2-fold increase in the Ins 1,4,5-P(3) concentration in the cytosol of the failing heart of CMPH was also observed.
Reduced SL level of PtdIns 4, 5-P(2) may severely jeopardize cardiac cell function in this hamster model of CHF. In addition, the profound changes in the profile of heart SL PLC isoenzyme could alter the complex second messenger responses of these isoenzymes, and elevated Ins 1,4,5-P(3) levels may contribute to intracellular Ca(2+) overload in the failing cardiomyocyte.
Cardiovascular Research 02/2001; 49(1):118-26. · 6.06 Impact Factor
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ABSTRACT: The beta-adrenoceptor (beta-AR) mediated signal transduction pathway in cardiomyocytes is known to involve beta1- and beta2-ARs, stimulatory (Gs) and inhibitory (Gi) guanine nucleotide binding proteins, adenylyl cyclase (AC) and cAMP-dependent protein kinase (PKA). The activation of beta1- and beta2-ARs has been shown to increase heart function by increasing Ca2+ -movements across the sarcolemmal membrane and sarcoplasmic reticulum through the stimulation of Gs-proteins, activation of AC and PKA enzymes and phosphorylation of the target sites. The activation of PKA has also been reported to increase phosphorylation of some myofibrillar proteins (for promoting cardiac relaxation) and nuclear proteins (for cardiac hypertrophy). The activation of beta2-AR has also been shown to affect Gi-proteins, stimulate mitogen activated protein kinase and increase protein synthesis by enhancing gene expression. Beta1- and beta2-ARs as well as AC are considered to be regulated by PKA- and protein kinase C (PKC)-mediated phosphorylations directly; both PKA and PKC also regulate beta-AR indirectly through the involvement of beta-AR kinase (betaARK), beta-arrestins and Gbeta gamma-protein subunits. Genetic manipulation of different components and regulators of beta-AR signal transduction pathway by employing transgenic and knockout mouse models has provided insight into their functional and regulatory characteristics in cardiomyocytes. The genetic studies have also helped in understanding the pathophysiological role of PARK in heart dysfunction and therapeutic role of betaARK inhibitors in the treatment of heart failure. Varying degrees of defects in the beta-AR signal transduction system have been identified in different types of heart failure to explain the attenuated response of the failing heart to sympathetic stimulation or catecholamine infusion. A decrease in beta1-AR density, an increase in the level of G1-proteins and overexpression of betaARK are usually associated with heart failure; however, these attenuations have been shown to be dependent upon the type and stage of heart failure as well as region of the heart. Both local and circulating renin-angiotensin systems, sympathetic nervous system and endothelial cell function appears to regulate the status of beta-AR signal transduction pathway in the failing heart. Thus different components and regulators of the beta-AR signal transduction pathway appears to represent important targets for the development of therapeutic interventions for the treatment of heart failure.
Molecular and Cellular Biochemistry 12/2000; 214(1-2):131-55. · 2.06 Impact Factor
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ABSTRACT: Phosphatidylinositol 4,5-bisphosphate (PtdIns 4,5-P2) is the substrate for phosphoinositide-phospholipase C (PLC) and is required for the function of several cardiac cell plasma membrane (sarcolemma, SL) proteins. PtdIns 4,5-P2 is synthesized in the SL membrane by coordinated and successive actions of PtdIns 4-kinase and PtdIns 4-phosphate 5-kinase. These kinases and the generation of PtdIns 4,5-P2 may be a factor in the cardiac dysfunction during pathophysiological conditions of oxidative stress. Therefore, we examined the effects of different reactive oxygen species (ROS) on the kinases' activities and subsequent generation of PtdIns 4,5-P2. Exposure to the xanthine-xanthine oxidase-ROS generating system significantly reduced both SL kinase activities. Superoxide dismutase did not prevent this inhibition; however, catalase significantly prevented the xanthine-xanthine oxidase induced inhibition. Treatment of SL with hydrogen peroxide (H2O2) resulted in inhibition of both the kinases, which was prevented by catalase and dithiothreitol (DTT). Hypochlorous acid also inhibited both the kinases, which was prevented by DTT. Deferoxamine (an iron chelator) and mannitol (an *OH scavenger) did not modify the H2O2-induced depression of the kinases, eliminating any role of *OH. Furthermore, the IC50 of H2O2 on PtdIns 4-kinase and PtdIns 4-P 5-kinase was 27 and 81 microM, respectively. In addition, inclusion of reduced glutathione in the assay of the kinases in the absence of H2O2 did not affect the activities of the kinases; however, oxidized glutathione induced a significant depression. Also, a significant decline of the PtdIns 4-kinase and PtdIns 4-P 5-kinase activities due to changing of the redox ratio was observed. Thiol modifiers (N-ethylmaleimide, methyl methanethiosulfonate, or p-chloromercuriphenylsulfonic acid) were detected to depress the kinases' activities, which were substantially prevented by DTT. The results suggest that functionally critical thiol groups may be associated with PtdIns 4-kinase and PtdIns 4-P 5-kinase and that changes of their redox state by ROS can impair their activities, which may be an important factor in the oxidant-induced cardiac dysfunction.
Archives of Biochemistry and Biophysics 11/2000; 382(1):48-56. · 2.93 Impact Factor
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ABSTRACT: The effects of propranolol and verapamil on contractile dysfunction, subcellular remodeling and changes in gene expression in cardiac hypertrophy due to pressure overload were examined. Rats were subjected to banding of the abdominal aorta and then treated with either propranolol (10 mg/kg daily), verapamil (5 mg/kg daily) or vehicle for 8 weeks after the surgery. Depression of the left ventricular function in the hypertrophied heart was associated with decreases in myofibrillar and myosin Ca2+ ATPase activities as well as Ca2+-pump and Ca2+-release activities of the sarcoplasmic reticulum (SR). The level of alpha-myosin heavy chain (alpha-MHC) mRNA was decreased while that of beta-MHC mRNA was increased in the pressure-overloaded heart. The level of SR Ca2+-pump ATPase (SERCA2) mRNA and protein content for SERCA2 were decreased in the pressure overloaded heart. Treatment of the hypertrophied animals with propranolol or verapamil resulted in preservation of the left ventricular function and prevention of the subcellular alterations. Shift in the alpha- and beta-MHC mRNA levels and changes in the expression in SERCA2 mRNA level and protein content were also attenuated by these treatments. The results suggest that blockade of beta-adrenoceptors or voltage-dependent calcium channels normalizes the cardiac gene expression, prevents subcellular remodeling and thus attenuates heart dysfunction in rats with cardiac hypertrophy. Furthermore, both cardiac beta-adrenoceptors and L-type Ca2+-channels may be involved in the genesis of cardiac hypertrophy due to pressure overload.
Molecular and Cellular Biochemistry 11/2000; 213(1-2):111-8. · 2.06 Impact Factor
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ABSTRACT: Myocardial ischemia-reperfusion represents a clinically relevant problem associated with thrombolysis, angioplasty and coronary bypass surgery. Injury of myocardium due to ischemia-reperfusion includes cardiac contractile dysfunction, arrhythmias as well as irreversible myocyte damage. These changes are considered to be the consequence of imbalance between the formation of oxidants and the availability of endogenous antioxidants in the heart.
An increase in the formation of reactive oxygen species during ischemia-reperfusion and the adverse effects of oxyradicals on myocardium have now been well established by both direct and indirect measurements. Although several experimental studies as well as clinical trials have demonstrated the cardioprotective effects of antioxidants, some studies have failed to substantiate the results. Nonetheless, it is becoming evident that some of the endogenous antioxidants such as glutathione peroxidase, superoxide dismutase, and catalase act as a primary defense mechanism whereas the others including vitamin E may play a secondary role for attenuating the ischemia-reperfusion injury. The importance of various endogenous antioxidants in suppressing oxidative stress is evident from the depression in their activities and the inhibition of cardiac alterations which they produce during ischemia-reperfusion injury. The effects of an antioxidant thiol containing compound, N-acetylcysteine, and ischemic preconditioning were shown to be similar in preventing changes in the ischemic-reperfused hearts.
The available evidence support the role of oxidative stress in ischemia-reperfusion injury and emphasize the importance of antioxidant mechanisms in cardioprotection.
Cardiovascular Research 09/2000; 47(3):446-56. · 6.06 Impact Factor
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ABSTRACT: In view of the critical role of intracellular Ca2 overload in the genesis of myocyte dysfunction and the ability of reactive oxygen species (ROS) to induce the intracellular Ca2+-overload, this article is concerned with analysis of the existing literature with respect to the role of oxidative stress in different types of cardiovascular diseases.
Oxidative stress in cardiac and vascular myocytes describes the injury caused to cells resulting from increased formation of ROS and/or decreased antioxidant reserve. The increase in the generation of ROS seems to be due to impaired mitochondrial reduction of molecular oxygen, secretion of ROS by white blood cells, endothelial dysfunction, auto-oxidation of catecholamines, as well as exposure to radiation or air pollution. On the other hand, depression in the antioxidant reserve, which serves as a defense mechanism in cardiac and vascular myocytes, appears to be due to the exhaustion and/or changes in gene expression. The deleterious effects of ROS are mainly due to abilities of ROS to produce changes in subcellular organelles, and induce intracellular Ca2+-overload. Although the cause-effect relationship of oxidative stress with any of the cardiovascular diseases still remains to be established, increased formation of ROS indicating the presence of oxidative stress has been observed in a wide variety of experimental and clinical conditions. Furthermore, antioxidant therapy has been shown to exert beneficial effects in hypertension, atherosclerosis, ischemic heart disease, cardiomyopathies and congestive heart failure.
The existing evidence support the view that oxidative stress may play a crucial role in cardiac and vascular abnormalities in different types of cardiovascular diseases and that the antioxidant therapy may prove beneficial in combating these problems.
Journal of Hypertension 07/2000; 18(6):655-73. · 4.02 Impact Factor
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ABSTRACT: Although Ca(2+)/calmodulin-dependent protein kinase II (CaMK II) is known to modulate the function of cardiac sarcoplasmic reticulum (SR) under physiological conditions, the status of SR CaMK II in ischemic preconditioning (IP) of the heart is not known. IP was induced by subjecting the isolated perfused rat hearts to three cycles of brief ischemia-reperfusion (I/R; 5 min ischemia and 5 min reperfusion), whereas the control hearts were perfused for 30 min with oxygenated medium. Sustained I/R in control and IP groups was induced by 30 min of global ischemia followed by 30 min of reperfusion. The left ventricular developed pressure, rate of the left ventricular pressure, as well as SR Ca(2+)-uptake activity and SR Ca(2+)-pump ATPase activity were depressed in the control I/R hearts; these changes were prevented upon subjecting the hearts to IP. The beneficial effects of IP on the I/R-induced changes in contractile activity and SR Ca(2+) pump were lost upon treating the hearts with KN-93, a specific CaMK II inhibitor. IP also prevented the I/R-induced depression in Ca(2+)/calmodulin-dependent SR Ca(2+)-uptake activity and the I/R-induced decrease in the SR CaMK II activity; these effects of IP were blocked by KN-93. The results indicate that IP may prevent the I/R-induced alterations in SR Ca(2+) handling abilities by preserving the SR CaMK II activity, and it is suggested that CaMK II may play a role in mediating the beneficial effects of IP on heart function.
AJP Heart and Circulatory Physiology 07/2000; 278(6):H1791-8. · 3.71 Impact Factor
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ABSTRACT: Although still scarcely studied, the phospholipid component of the cell membrane is of absolute importance for cell function. Experimental evidence indicates that individual molecular species of a given phospholipid can influence specific membrane functions. We have examined the changes in molecular species of diacyl and alkenylacyl choline/ethanolamine glycerophospholipid subclasses and those of phosphatidylserine in purified cardiac sarcolemma of healthy and streptozotocin-induced insulin dependent diabetic rats without or with insulin treatment. The relative content of plasmalogens increased in all the phospholipid classes of diabetic sarcolemma under study. Phosphatidylcholine and phosphatidylethanolamine were mostly enriched with molecular species containing linoleic acid in sn-2 position and deprived of the molecular species containing arachidonic acid. The molecular species of phosphatidylserine containing either arachidonic or docosahexaenoic acid were less abundant in membranes from diabetic rats than in membranes from controls. Insulin treatment of diabetic rats restored the species profile of phosphatidylethanolamine and overcorrected the changes in molecular species of phosphatidylcholine. The results suggest that the high sarcolemmal level of plasmalogens and the abnormal molecular species of glycerophospholipids may be critical for the membrane dysfunction and defective contractility of the diabetic heart.
Journal of Molecular and Cellular Cardiology 07/2000; 32(6):1061-74. · 5.17 Impact Factor
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ABSTRACT: This study examined the status of sarcolemmal Na+/K+-ATPase activity in rat heart under conditions of Ca2+-paradox to explore the existence of a relationship between changes in Na+/K+-pump function and myocardial Na+ as well as K+ content. One min of reperfusion with Ca2+ after 5 min of Ca2+-free perfusion reduced Na+/K+-ATPase activity in the isolated heart by 53% while Mg2+-ATPase, another sarcolemmal bound enzyme, retained 74% of its control activity. These changes in sarcolemmal ATPase activities were dependent on the duration and Ca2+ concentration of the initial perfusion and subsequent reperfusion periods; however, the Na+/K+-ATPase activity was consistently more depressed than Mg2+-ATPase activity under all conditions. The depression in both enzyme activities was associated with a reduction in Vmax without any changes in Km values. Low Na+ perfusion and hypothermia, which protect the isolated heart from the Ca2+-paradox, also prevented reperfusion-induced enzyme alterations. A significant relationship emerged upon comparison of the changes in myocardial Na+ and K+ content to Na+/K+-ATPase activity under identical conditions. At least 60% of the control enzyme activity was necessary to maintain normal cation gradients. Depression of the Na+/K+-ATPase activity by 60-65% resulted in a marked increase and decrease in intracellular Na+ and K+ content, respectively. These results suggest that changes in myocardial Na+ and K+ content during Ca2+-paradox are related to activity of the Na+/K+-pump; the impaired Na+/K+-ATPase activity may lead to augmentation of Ca2+-overload via an enhancement of the Na+/Ca2+-exchange system.
Molecular and Cellular Biochemistry 05/2000; 207(1-2):87-94. · 2.06 Impact Factor
