Myocardial Mitochondria Research Articles

E0133 Influence of telmisartan on oxidative stress parameters in streptozotocin-induced type 1 diabetic rats

ObjectiveTo investigate the level of oxidative stress in streptozotocin-induced type 1 diabetic rats as well as the intervention effects of telmisartan.MethodsDiabetic rat models were established by intraperitoneal injection of streptozotocin...

E0014 The role of peroxisome proliferatoractivated receptor coactivator 1 in myocardial ischaemic preconditioning and diazoxide preconditioning

ObjectiveIschemic preconditioning (IPC) is an important endogenous protective mechanism for ischaemia-reperfusion (I/R) injury. Currently, it is believed that opening of the mitochondrial ATP-sensitive potassium channel (mitoKATP channel) plays an important...

Myocardial 99mTc-sestamibi extraction and washout in hypertensive heart failure using an isolated rat heart

Myocardial mitochondria are the primary part of energy production for healthy cardiac contraction. And mitochondrial dysfunction would play an important role in progressive heart failure. In the recent years, myocardial washout of (99m)Tc-sestamibi [((99m)Tc-hexakis-2-methoxy-2-methylpropyl isonitrile (MIBI)] has been introduced to be a potential marker in patients with heart failure. The objective of this study was to clarify MIBI extraction and washout kinetics using isolated perfusion system in hypertension induced model of myocardial dysfunction. Six-week-old Dahl-salt sensitive rats, allotted to 4 groups; a 5-week high-salt group (5 wk-HS), 12-week high-salt group (12 wk-HS) and two age-matched, low-salt diet control groups (5 wk-LS and 12 wk-LS). The rats in 5 wk-HS and 12 wk-HS groups were fed a high-salt diet (containing 8% NaCl). Cardiac function was examined by echocardiography before removing heart. Hearts were perfused according to the Langendorff method at a constant flow rate, in which 20-min MIBI washin was conducted followed by 25-min MIBI washout. Whole heart radioactivity was collected every sec by an external gamma detector. The myocardial extraction, K(1) (ml/min) and washout rate, k(2) (min(-1)) were generated. High-salt diet groups showed significant high-blood pressure. Echocardiography revealed thickened LV walls in 5 wk-HS, and reduced cardiac function in 12 wk-HS, compared to each age-matched control group. K(1) showed no significant difference among all groups (5 wk-HS: 2.36 ± 1.07, 5 wk-control: 2.59 ± 0.28, 12 wk-HS: 1.91 ± 0.90, and 12 wk-control: 2.84 ± 0.57). k(2) in 5 wk-HS was comparable to that in the age matched control group (0.00030 ± 0.00039 vs -0.000010 ± 0.00044), but it was increased remarkably in 18 wk-HS compared to the age matched control group (0.0025 ± 0.0011 vs 0.000025 ± 0.000041, P<.01), and 5 wk-HS (P<.01). In the course of hypertensive heart disease, MIBI washout was increased in the transitional state from hypertrophied to dilated and failing heart, while MIBI extraction remained intact.

Effect of nicorandil pretreatment on myocardial mitochondria in a rabbit model of myocardial ischemia-reperfusion

Objective To investigate the effect of nicorandil pretreatment on myocardial mitochondria in a rabbit model of myocardial ischemia-reperfusion (I/R). Methods Tirty-two healthy male New Zealand white rabbits weighing 2.0-2.5 kg aged 4 months were randomly allocated into 4 groups ( n = 8 each): Ⅰ group sham operation (group S); Ⅱ group I/R; Ⅲ group nicorandil pretreatment (group N) and Ⅳ group nicorandil + 5 hydroxydecanoic acid (group N + 5-HD). Myocardial I/R was induced by 30 min occlusion of left circumflex coronary artery followed by 120 min reperfusion. In group N and N + 5-HD a bolus of nicorandil 100 μg/kg was given iv at 10 min before myocardial ischemia followed by continuous infusion at 10 μg· kg-1 · min-1 until the beginning of myocardial ischemia. In group Ⅳ a bolus of 5-HD 5 mg/kg was injected iv at 20 min before myocardial ischemia.The animals were sacrificed at the end of 120 min reperfusion. The mitochondrial membrane potential was measured by flow cytometry using JC-1 fluorescence probe as indicator. Bcl-2, Bax and cytochrome c protein expression was determined by immuno-histochemistry. Myocardial ultrastructure was examined with transmission electron microscope. Results Red fluovescence intensity indicating normal live cells was significantly higher, the green fluorescence intensity indicating apoptotic cells was lower and red/green fluorescence intensity ratio was higher; the Bcl-2/Bax ratio was significantly higher and cytochrome c protein expression lower in group N than in group I/R.5-HD administration negated the protective effect of nicorandil pretreatment against myocardial I/R injury. Conclusion Nicorandil stabilizes mitochondrial membrane potential, decreases cytochrome c protein releasing, and suppresses mitochondrial apoptotic signal transduction by opening the mito-KATP channels. Key words: Nicorandil; Myocardial reperfusion injury; Mitochondria,heart

Androgen Receptor Counteracts Doxorubicin-Induced Cardiotoxicity in Male Mice

Doxorubicin (Dox) has been used as a potent anticancer agent, but serious cardiotoxicity precludes its use in a wide range of patients. We have reported that the androgen-androgen receptor (AR) system plays important roles in cardiac growth and protection from angiotensin II-induced cardiac remodeling. The present study was undertaken to clarify whether the androgen-AR system exerts a cardioprotective effect against Dox-induced cardiotoxicity. Male AR knockout (ARKO) and age-matched littermate male wild-type (WT) mice at 25 wk of age were given ip injections of Dox (20 mg/kg) or a vehicle. The survival rate and left ventricular function in Dox-treated male ARKO mice were reduced compared with those in Dox-treated male WT mice. Electron microscopic study showed prominent vacuole formation of myocardial mitochondria in Dox-treated male ARKO mice. Cardiac oxidative stress and apoptosis of cardiomyocytes were increased more prominently by Dox treatment in male ARKO mice than in male WT mice. In addition, Dox-induced reduction in the expression of cardiac mitochondria transcription factor A (Tfam) and phosphorylation of serine-threonine kinase (Akt) was more pronounced in male ARKO mice than in male WT mice. In cardiac myoblast cells, testosterone up-regulated Akt phosphorylation and Tfam expression and exerted an antiapoptotic effect against Dox-induced cardiotoxicity. Collectively, the results demonstrate that Dox-induced cardiotoxicity is aggravated in male ARKO mice via exacerbation of mitochondrial damage and superoxide generation, leading to enhanced apoptosis of cardiomyocytes. Thus, the androgen-AR system is thought to counteract Dox-induced cardiotoxicity partly through activation of the Akt pathway and up-regulation of Tfam to protect cardiomyocytes from mitochondrial damage and apoptosis.

Opioid δ 1 and δ 2 Receptor Agonist Attenuate Myocardial Injury Via mPTP in Rats With Acute Hemorrhagic Shock

Studies have documented the beneficial roles of δ opioid receptor (OR) agonist for hemorrhagic shock. However, the myocardial protection roles and the mechanisms of hemodynamic stability during resuscitation of δ-OR agonist have not been explored. This study was designed to investigate myocardial protective effects and the mechanisms of high selective δ(1) and δ(2)-OR agonists during resuscitation of acute hemorrhagic shock. Forty-eight adult male SD rats were adopted 60-min hemorrhagic shock through removing 30% (5 mL) of the total blood volume, and followed by 2-h resuscitation with shed blood and L-lactated Ringer's solution. At the end of shock and prior to resuscitation, NS, δ(1)-OR agonist TAN-67 (10 mg/kg) and antagonist BNTX (3 mg/kg), and BNTX+TAN-67, DMSO, δ(2)-OR agonist Deltorphin II (1 mg/kg) and antagonist NTB (2 mg/kg), and NTB+Deltorphin II in 0.5 mL were administrated. Left ventricular function parameters were measured during the whole experimental period. Myocardial mitochondria were isolated to determine opening of mitochondrial permeability transition pore (mPTP). Morphologic changes in myocardium and mitochondria were observed by electron microscope. The hemodynamic indexes in group TAN-67 and group Deltorphin II were higher than control group at each time point during resuscitation, respectively (P<0.05). TAN-67 and Deltorphin II decrease but their antagonists BNTX and NTB increase the opening of mPTP (P<0.05). Myocardial and mitochondrial damage were attenuated in group TAN-67 and group Deltorphin II. δ(1)-OR agonist TAN-67 and δ(2)-OR agonist Deltorphin II protect the heart by targeting the mPTP in rats with acute hemorrhagic shock.

Effect of complexes of precursors and modulators of coenzyme q biosynthesis on functional state of old rats' heart mitochondria

Our research demonstrate that ageing leads to changes in activity of electron-transporting enzyme complexes in myocardial mitochondria of old rats and to increased sensitivity of mitochondrial permeability transition pore to inductors of its opening - Ca2+ and phenylarsine oxide. We also observed activation of lipid and protein free-radical peroxidation processes. Administration of a complex of biologically active substances that included precursors and modulators of coenzyme Q biosynthesis (α-tocopherol acetate, 4-hydroxybenzoic acid, and methionine) we observed the increase in coenzyme Q content, correction of functional activity of mitochondrial electron-transport chain enzyme complexes, the decrease in intensivity of lipid and protein free-radical peroxidation in the heart and the decrease in sensitivity of mitochondrial permeability transition pore to inductors of its opening. This complex may be used to treat mitochondrial dysfunction under numerous pathologies of cardiovascular system, as well as in ageing.

The effect of complexes of precursors and modulators of coenzyme Q biosynthesis on the functional state of heart mitochondria of old rats

Aging is accompanied by changes in activity of electron-transport enzyme complexes in myocardial mitochondria of old rats and by increased sensitivity of the mitochondrial permeability transition pore (MPTP) to inductors of its opening (Ca2+ and phenylarsine oxide). We also observed activation of lipid and protein free-radical peroxidation processes. Administration of a complex of biologically active substances that included precursors and modulators of coenzyme Q biosynthesis (α-tocopherol acetate, 4-hydroxybenzoic acid, and methionine) caused the increase in coenzyme Q content, correction of functional activity of mitochondrial electron-transport chain enzyme complexes, the decrease in intensity of lipid and protein free-radical peroxidation in the heart mitochondria and the decrease in sensitivity of mitochondrial permeability transition pore to inductors of its opening. This complex may be recommended for treatment of mitochondrial dysfunction in various pathologies of cardiovascular system, including in aging.

Vibration Model for Hypoxic Type of Cell Metabolism Evaluated on Rabbit Cardiomyocytes

Activity of the energy production system in rabbits myocardium was examined under various conditions of whole-body vibration. The energy-dependent response of native mitochondria from rabbit heart was studied polarographically using a Clark closed membrane electrode. In was established that the energy production system in rabbit myocardium was involved in organism's response to whole-body vibration. Functional changes in myocardial mitochondria were shown to depend on the mode of whole-body vibration (frequency and duration). It manifested in an imbalance between functional activity of FAD- and NAD-dependent components of the respiratory chain. The increase in the frequency and duration of vibration was accompanied by dysfunction of the energy production system in cardiomyocytes. These changes manifested in activation of succinic acid oxidation and inhibition of NAD-dependent components of the mitochondrial respiratory chain. Vibration due to systemic dysregulatory influence can be used as a model for studies of both vibration phenomenon realized at the level of the energy production system in organs and tissues and vibroprotective properties of medicinal products.

Insulin stimulates Akt translocation to mitochondria: Implications on dysregulation of mitochondrial oxidative phosphorylation in diabetic myocardium

Mitochondrial oxidative phosphorylation is the major source of energy in cardiac muscle. In the streptozotocin-induced diabetic (STZ-DM) mice, myocardial oxidative phosphorylation was perturbated and oxidative phosphorylation complex V (ATP synthase) activity was significantly reduced. To determine the independent effects of hyperglycemia and insulin deficiency on the changes of myocardial complex V, we used phlorizin (Ph) to normalize blood glucose in the diabetic mice. Ph treatment did not improve myocardial complex V activity in the STZ-DM mice, whereas insulin treatment normalized myocardial complex V activity in the diabetic mice. Therefore, the reduction of complex V activity was caused by insulin deficiency and not by hyperglycemia in STZ-DM myocardium. Acute insulin stimulation induced phosphorylation of Akt and translocation of Akt to mitochondria in myocardium. Translocation of phospho-Akt to mitochondria was enhanced in the STZ-DM mice and was blunted in the diet-induced diabetic mice. In parallel, insulin activation of complex V was enhanced in the STZ-DM myocardium and suppressed in the diet-induced diabetic myocardium. In vivo inhibition of Akt blocked insulin stimulation of phospho-Akt translocation and blunted activation of complex V. Insulin-activated Akt translocation to mitochondria in cardiac muscle is a novel paradigm that may have important implications on myocardial bioenergetics.

Effects of Fusarium Mycotoxin Butenolide on Myocardial Mitochondria In Vitro

Fusarium mycotoxin toxicosis has been implicated in the etiology of Keshan disease, an endemic mitochondrial cardiomyopathy prevailing in certain areas of China. Butenolide (4-acetamido-4-hydroxy-2-butenoic acid γ-lactone) is one of the Fusarium mycotoxins which are frequently detected from cereal grains in endemic areas. A recent study indicates that this mycotoxin induces rat cardiotoxicity, but its effect on the myocardial mitochondria remains unclear. The present study is therefore undertaken to explore the toxic effect potential of butenolide on the myocardial mitochondria. Exposure of cultured cardiac myocytes to 50 μg/ml of butenolide provoked dissipation of mitochondrial membrane potential. Incubation of isolated rat myocardial mitochondria with butenolide of 100 μg/ml for 60 min resulted in mitochondrial swelling, indicating the occurrence of mitochondrial permeability transition. Furthermore, marked oxidative damage in myocardial mitochondria was observed after incubation of isolated myocardial mitochondria with butenolide ranging from 0 to 50 μg/ml for 60 min, as manifested by concentration-dependent increases in the production of thiobarbituric acid reactive substances, the indicator of lipid peroxidation. Contrarily, a representative antioxidant glutathione significantly alleviated this oxidative mitochondrial damage induced by butenolide. In conclusion, these observations clearly show that butenolide can induce dysfunction of myocardial mitochondria, and oxidative damage appears to play a crucial role in these deleterious effects. The present study supports the hypothesis that mycotoxin toxicosis is a probable etiological factor of Keshan disease, the mitochondrial cardiomyopathy.

Breviscapine, a traditional Chinese medicine, alleviates myocardial ischaemia reperfusion injury in diabetic rats

Objective — The aim of this study was to explore the effects of breviscapine on the expressions of intercellular adhesion molecule-1(ICAM-1), ATPase activities and oxidative stress in ischaemia-reperfused (I/R) myocardium of diabetic rats.Methods — Sprague Dawley rats were randomly divided into two groups (a diabetic group and a non-diabetic group), and each group divided into two subgroups including a control group and a breviscapine group. Reperfusion surgery was carried out in all rats. The contents of malonaldehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) in serum and myocardial tissues were measured.The activities of Na+-K+-ATPase, Mg2+-ATPase, Ca2+-ATPase in myocardial mitochondria were measured. The ICAM-1 protein expressions in myocardium were determined with the immunohistochemical method.Results — The activities of Na+-K+-ATPase, Mg2+-ATPase, Ca2+-ATPase were significantly increased in diabetic rats in the breviscapine group compared with the control group. Compared with the non-diabetic control group, the contents of MDA in serum and myocardium were significantly increased in the diabetic control group. Breviscapine led to a reduction of the contents of MDA in the diabetic and non-diabetic group. Compared with the non-diabetic control group, the activities of SOD and GSH-PX in the myocardium were significantly decreased in the diabetic control group. The activities of SOD and GSH-PX in serum and myocardium were increased in the diabetic and nondiabetic group after breviscapine treatment. Compared with the non-diabetic control group, the ICAM-1 protein expressions were increased significantly in the diabetic control group. Breviscapine decreased the ICAM-1 protein expression in the diabetic and the non-diabetic group.Conclusion — Breviscapine may have protective effects on myocardial ischaemia reperfusion injury of diabetic rats by scavenging oxygen free radicals, decreasing the expressions of ICAM-1 protein in myocardium and increasing the activities of Na+-K+-ATPase, Mg2+-ATPase, Ca2+-ATPase in myocardial mitochondria.

Abstract 4031: Nitric Oxide Synthase 3 Deficiency Worsens Myocardial Dysfunction and Survival in Murine Polymicrobial Sepsis

Background: Myocardial dysfunction during sepsis contributes to the high mortality of patients with septic shock. The role of NOS3 on cardiac function during sepsis remains incompletely understood. Here, we examined impact of NOS3 deficiency on myocardial function and survival during peritonitis-induced polymicrobial sepsis. Methods: Severe polymicrobial sepsis was induced by colon ascendens stent peritonitis (CASP) in wild-type (WT) and NOS3 deficient (KO) mice. Cardiac function was examined both in vivo hemodynamic study and in isolated left ventricular cardiomyocytes, where sarcomere length (SL) and intracellular calcium transients ([Ca 2+ ] i ) were measured by video-edge detection and Fura-2 fluorescence, respectively. Mitochondrial function was assessed by measuring the ATP production rate in isolated mitochondria from left ventricle. Results: Mortality at 24 hours after CASP was higher in KO (15/15, 100%) than in WT (13/20, 65%, P&lt;0.05 vs KO). In vivo hemodynamic study 22 hours after CASP revealed both systolic and diastolic cardiac functions were impaired to a greater extent in KO than in WT. In isolated cardiomyocytes, CASP induced-reduction in percent SL shortening and the peak amplitude of [Ca 2+ ] i was more marked in NOS3KO than in WT. The time constants for SL relengthening and diastolic [Ca 2+ ] i decay were prolonged to a greater extent in KO than in WT after CASP. Cardiac inflammation estimated by expression levels of inflammatory cytokines (TNF-α, IL-1β, IL-6) was more pronounced in KO than in WT. CASP-induced reduction in ATP production rate of myocardial mitochondria was more marked in KO than in WT, which was associated with reduction in mitochondrial complex I activity. Conclusions: These results suggest that NOS3 deficiency aggravates myocardial dysfunction through mitochondrial dysfunction and decreases survival after peritonitis-induced polymicrobial sepsis in mice. Table Hemodynamic and myocyte study 22 hours after CASP or sham

The role of oxidative stress in the development of congestive heart failure in a chicken genotype selected for rapid growth

The present study examined the possible role of reactive oxygen species in the pathogenesis of heart failure in broilers. Data were collected from three groups of birds at various risk of heart failure: Leghorn chickens (resistant to heart failure), slow-growing feed-restricted broilers (low risk of heart failure), fast-growing ad libitum fed broilers (high risk of heart failure), and broilers with congestive heart failure (CHF). In the first part of the study, basic clinical parameters and ultrastructural changes were examined in the context of lipid peroxidation of the ventricular myocardium. This was followed by the study of in vitro changes in the activity of selected cytosolic enzymes (creatine kinase and lactate dehydrogenase) and mitochondrial enzymes (pyruvate dehydrogenase and α-ketoglutarate dehydrogenase) in the presence of oxidants (hydrogen peroxide or tertiary butyl hydroperoxide). The distinctive clinical feature in the fast-growing broilers and in the broilers with CHF as compared with slow-growing broilers or Leghorn chickens was a significantly lower heart rate (P <0.05). Electron microscopy revealed marked morphological changes in myocardial mitochondria in these broilers (i.e. fast-growing broilers and broilers with CHF). The level of malondialdehyde equivalents, an indicator of lipid peroxidation subsequent to generated oxidative stress, was significantly higher (P <0.05) in ad libitum fed broilers and was highest (P <0.01) in broilers with CHF. In vitro, the presence of oxidants had a detrimental effect on creatine kinase and α-ketoglutarate dehydrogenase activity, while lactate dehydrogenase activity increased. The activity of pyruvate dehydrogenase was not altered by oxidants. Our results indicate that the deterioration of heart function in fast-growing commercial broilers in our experimental model is associated with oxidative stress leading to lipid peroxidation of cellular and mitochondrial membranes, and decreased activity of myocardial creatine kinase and α-ketoglutarate dehydrogenase enzymes critical for energy synthesis and transformation pathways.

Fullerene–Interfaced Porphyrin Ligand in Affinity Chromatography of Membrane Proteins

To purify the mammalian cell membrane porphyrin binding proteins (PBP), an original affinity chromatographic technique is proposed. The method is based on the application of an agarose attached fullerene-porphyrin ligand connected to a polysaccharide gel matrix through the epoxy-cyclohexyl residue interface. A selective PBP-stationary phase coupling has been managed in a single column chromatographic run leading to a complete purification of the 17.6 kDa monomer protein from the rat myocardium mitochondria membranes. A synchronous pH and ionic strength linear gradients were used to separate this protein with a high specific affinity to the porphyrin K related structures from all non-specific sorption retained membrane proteins.

QS232. Ischemic Preconditioning Selectively Protects Interfibrillar Mitochondria by Preserving Cytochrome C

Purpose: Myocardial mitochondria are grouped into two distinct populations: interfibrillar (IF) and subsarcolemmal (SS) mitochondria. While ischemic preconditioning (IPC) protects overall mitochondrial (mito) function during ischemia-reperfusion (IR), it is unclear whether it has a differential effect on those two mitochondrial populations. The purpose of this study was to elucidate the effects of IPC on IF and SS mitochondria. Method: Isolated rat hearts (n=5/group) were subjected to either a) 40 minutes (min) of equilibration (EQ), 30 min of ischemia (I), and 30 min of reperfusion (RP) (CONTROL) or b) 10 min of EQ, three 5 min episodes of IPC, 30 min I, and 30 min of RP (IPC group). Left ventricular developed pressure (DP) was measured. Mitochondria respiration (state 2, 3, 4, and respiratory control index (state 3/4)) was measured by polarography using glutamate and malate as substrates. Cytochrome c concentration was measured by HPLC. Data is expressed as mean±SEM. Conclusion: Ischemia reperfusion damages IF mitochondria more than SS mitochondria as evidenced by lower cytochrome c levels during reperfusion. IPC protects both IF and SS mitochondria function as evidenced by improved state 3 and RCI. The mechanism of protection of IF mitochondria by IPC may be related to selective preservation of cytochrome c levels during reperfusion.

Effect of carni Q-gel (ubiquinol and carnitine) on cytokines in patients with heart failure in the Tishcon study

Introduction —There is evidence that both carnitine and coenzyme Q10 (Co Q), which are important for the functioning of myocardial mitochondria, are deficient in patients with congestive heart failure, in association with increased pro-inflammatory cytokines. It is possible that supplementation with ubiquinol and L-carnitine may protect these patients by decreasing inflammation.Subjects and methods — In a randomized, double-blind, placebo-controlled trial, the effects of carni Q-gel (2250 mg/d L-carnitine and 270 mg/d hydrosoluble ubiquinol) were examined for 12 weeks.Thirty-one patients with heart failure received intervention (group A) and another 31 patients served as controls (group B). Serum levels of interleukin (IL)-6, tumour necrosis factor (TNF)-alpha and IL-10 could be studied among 29 patients in each group. Statistical analysis was conducted by analysis of variance and chi square test.Results — Echocardiography ejection fractions were lower at baseline (38.8 + 7.6 vs. 39.3 + 6.7% in the intervention and control groups, respectively) among both group of patients, indicating class II-IV heart failure. Serum concentration of interleukin-6 (IL-6), a pro-inflammatory cytokine, was high (18.7 ± 5.8 vs. 15.0 + 3.3 pg/ml, normal 0.0-3.9) and IL-10 (anti-inflammatory) was normal (3.4 ± 1.5 vs. 2.9 ± 1.0 pg/ml, the normal range is 1.5-3.1 pg/ml) in both groups at baseline.After 12 weeks, there was a marked reduction in IL-6 in the intervention group without such changes in the control group (7.6 ± 1.5 vs. 11.4 ± 2.5 pg/ml, P< 0.01. IL-10 showed only the non-significant decrease in both groups from the baseline levels (3.2 ± 1.0 vs. 2.8 ± 0.9 pg/ml).TNF-alpha, which was comparable at baseline (17.6 ± 4.3 vs. 20.0 ± 5.3 pg/ml), also showed a greater decline in the carni Q-gel group compared to the placebo group (12.5 ± 3.3 vs. 17.2 ± 3.2 pg/ml, P< 0.05). Baseline serum CoQ levels (0.21 ± 0.11 vs. 0.19 ± 0.10 μg/ml) were low; however, after 12 weeks, serum CoQ showed a significant increase in the carni Q-gel group as compared to the control group (2.7 ± 1.2 and 0.76 ± 0.14 μg/ml, respectively). After 12 weeks of treatment, the quality of life visual analogous scale revealed that dyspnoea, palpitation and fatigue, (NYHA class II-III-IV), which were present at rest in all patients at baseline, showed beneficial effects in the intervention group compared to the placebo group. The six-minute walk test showed that there was a significant greater benefit in walking, from the baseline distance in the intervention group (208 ± 15.8 vs. 281 ± 20.6 metres, P<0.02) compared to the placebo group (218.4 ± 17.6 vs. 260.7 ± 19.3 metres, P < 0.05). The symptom scale indicated that the majority of patients showed improvement in the intervention group compared to the control group (28 vs. 16 patients, respectively, P< 0.05).Three patients in the intervention group had nausea and vomiting, which were controlled with symptomatic treatment.Conclusions — These findings indicate that treatment with ubiquinol + L-carnitine can cause a significant reduction in the pro-inflammatory cytokines that are neurohumoural precursors related to sympathetic and parasympathetic activity, which is impaired in patients with heart failure. There was no adverse effect on IL-10.There was a significant improvement in quality of life as well as decrease in NYHA-defined heart failure.

Exercise training decreases rat heart mitochondria free radical generation but does not prevent Ca2+-induced dysfunction

Exercise provides cardioprotection against ischemia-reperfusion injury, a process involving mitochondrial reactive oxygen species (ROS) generation and calcium overload. This study tested the hypotheses that isolated mitochondria from hearts of endurance-trained rats have decreased ROS production and improved tolerance against Ca(2+)-induced dysfunction. Male Fischer 344 rats were either sedentary (Sed, n = 8) or endurance exercise trained (ET, n = 11) by running on a treadmill for 16 wk (5 days/wk, 60 min/day, 25 m/min, 6 degrees grade). Mitochondrial oxidative phosphorylation measures were determined with glutamate-malate or succinate as substrates, and H(2)O(2) production and permeability transition pore (PTP) opening were determined with succinate. All assays were carried out in the absence and presence of calcium. In response to 25 and 50 microM CaCl(2), Sed and ET displayed similar decreases in state 3 respiration, respiratory control ratio, and ADP:O ratio. Ca(2+)-induced PTP opening was also similar. However, H(2)O(2) production by ET was lower than Sed (P < 0.05) in the absence of calcium (323 +/- 12 vs. 362 +/- 11 pmol.min(-1).mg protein(-1)) and the presence of 50 microM CaCl(2) (154 +/- 3 vs. 197 +/- 7 pmol.min(-1).mg protein(-1)). Rotenone, which blocks electron flow from succinate to complex 1, reduced H(2)O(2) production and eliminated differences between ET and Sed. Mitochondrial superoxide dismutase and glutathione peroxidase were not affected by exercise. Catalase activity was extremely low but increased 49% in ET (P < 0.05). In conclusion, exercise reduces ROS production in myocardial mitochondria through adaptations specific to complex 1 but does not improve mitochondrial tolerance to calcium overload.

Endogenous ghrelin increases in adriamycin-induced heart failure rats

Evidence has indicated that plasma ghrelin was elevated in chronic heart failure (CHF) patients with cachexia. The present report studied whether pathophysiologic increment of endogenous ghrelin levels was existed in the progression of adriamycin (ADR)-induced CHF, then the possible compensatory mechanism by which the changes were induced and the relationship between active ghrelin, cardiac function and energy reserve in heart failure (HF) rats were explored. Cardiac function, high energy phosphates (HEP) content, and ghrelin levels in plasma and myocardium were measured at 4 days, 1, 2 and 3 weeks after the last injection of ADR, after which correlation analysis was performed between these markers in HF rats. Results showed that cardiac function decreased early, then was significantly restored and worsened at 3 weeks accompanied by the decrease of myocardial ATP content. Plasma ghrelin level increased significantly at each time point while myocardial ghrelin level increased transiently, then was restored followed by increased oxidative stress status and apoptosis in the weakening heart. Moreover, correlation analysis indicated that the markers of cardiac function and HEP were positively correlated to the endogenous ghrelin levels at the HF stage. This study indicated that the increase of endogenous ghrelin levels during the progression of the HF induced by ADR represent a compensatory self-protective effect by improving cardiac function and retaining myocardial energy reserve; this may be closely linked to anti-oxidative and anti-apoptosis mechanisms through regulating myocardial mitochondria function by ghrelin; but further investigations are necessary.

Cardiac mitochondrial damage and loss of ROS defense after burn injury: the beneficial effects of antioxidant therapy.

Mechanisms of burn-related cardiac dysfunction may involve defects in mitochondria. This study determined 1) whether burn injury alters myocardial mitochondrial integrity and function; and 2) whether an antioxidant vitamin therapy prevented changes in cardiac mitochondrial function after burn. Sprague-Dawley rats were given a 3 degrees burn over 40% total body surface area and fluid resuscitated. Antioxidant vitamins or vehicle were given to sham and burn rats. Mitochondrial and cytosolic fractions were prepared from heart tissues at several times postburn. In mitochondria, lipid peroxidation was measured to assess oxidative stress, mitochondrial outer membrane damage and cytochrome-c translocation were determined to estimate mitochondrial integrity, and activities of SOD and glutathione peroxidase were examined to evaluate mitochondrial antioxidant defense. Cardiac function was measured by Langendorff model in sham and burn rats given either vitamins or vehicle. Twenty-four hours postburn, mitochondrial outer membrane damage was progressively increased to approximately 50%, and cytosolic cytochrome-c gradually accumulated to approximately three times more than that measured in shams, indicating impaired mitochondrial integrity. Maximal decrease of mitochondrial SOD activity occurred 8 h postburn ( approximately 63.5% of shams), whereas maximal decrease in glutathione peroxidase activity persisted 2-24 h postburn ( approximately 60% of shams). In burn animals, lipid peroxidation in cardiac mitochondria increased 30-50%, suggesting burn-induced oxidative stress. Antioxidant vitamin therapy prevented burn-related loss of membrane integrity and antioxidant defense in myocardial mitochondria and prevented cardiac dysfunction. These data suggest that burn-mediated mitochondrial dysfunction and loss of reactive oxygen species defense may play a role in postburn cardiac dysfunction.