Myocardial ATP Content Research Articles

Q50, an Iron-Chelating and Zinc-Complexing Agent, Improves Cardiac Function in Rat Models of Ischemia/Reperfusion-Induced Myocardial Injury

Reperfusion of ischemic myocardium may contribute to substantial cardiac tissue damage, but the addition of iron chelators, zinc or zinc complexes has been shown to prevent heart from reperfusion injury. We investigated the possible beneficial effects of an iron-chelating and zinc-complexing agent, Q50, in rat models of ischemia/reperfusion (I/R)-induced myocardial infarction and on global reversible myocardial I/R injury after heart transplantation. Rats underwent 45-min myocardial ischemia by left anterior descending coronary artery ligation followed by 24h reperfusion. Vehicle or Q50 (10 mg/kg, IV) were given 5 min before reperfusion. In a heart transplantation model, donor rats received vehicle or Q50 (30 mg/kg, IV) 1h before the onset of ischemia. In myocardial infarcted rats, increased left ventricular end-systolic and end-diastolic volumes were significantly decreased by Q50 post treatment as compared with the sham group. Moreover, in I/R rat hearts, the decreased dP/dtmax and load-independent contractility parameters were significantly increased after Q50. However, Q50 treatment did not reduce infarct size or have any effect on increased plasma cardiac troponin-T-levels. In the rat model of heart transplantation, 1h after reperfusion, decreased left ventricular systolic pressure, dP/dt(max), dP/dt(min) and myocardial ATP content were significantly increased and myocardial protein expression of superoxide dismutase-1 was upregulated after Q50 treatment. In 2 experimental models of I/R, administration of Q50 improved myocardial function. Its mechanisms of action implicate in part the restoration of myocardial high-energy phosphates and upregulation of antioxidant enzymes.

Which Is the Better Option During Neonatal Cardiopulmonary Bypass

The optimal myocardial protection strategy for newborns/infants undergoing congenital heart surgery remains controversial. The purpose of this study was to compare myocardial protection using histidine-tryptophan-ketoglutarate (HTK) and cold blood cardioplegia in a neonatal piglet model. Twenty-one piglets were randomized to three groups: the control group (C group, n = 7), a single dose of HTK group (H group, n = 7), and multidose cold blood cardioplegia group (B group, n = 7). Animals in the two experimental groups were placed on hypothermic cardiopulmonary bypass, after which the ascending aorta was clamped for 2 hours. Immediately after declamping, both the difference between arterial and coronary sinus blood lactate concentrations and the oxygen extraction did not differ between the H group and the B group. At 3 hours after declamping, rise in serum troponin-T and creatine kinase isoenzyme MB levels showed no significant differences between the H group and the B group (p = 0.735 and p = 0.103, respectively). No significant differences were noted in the myocardial lactate content, ATP content, and histopathological score between the H group and the B group (p = 0.810, p = 0.158, and p = 0.399, respectively). Transfusion requirement in the B group was significantly more than that in the H group (p = 0.003). HTK solution provides equivalent myocardial protection to multidose cold blood cardioplegia for the neonatal heart with less transfusion requirement.

Effects of glycine supplementation on myocardial damage and cardiac function after severe burn

BackgroundGlycine has been shown to participate in protection from hypoxia/reoxygenation injury. However, the cardioprotective effect of glycine after burn remains unclear. This study aimed to explore the protective effect of glycine on myocardial damage in severely burned rats. MethodsSeventy-two Wistar rats were randomly divided into three groups: normal controls (C), burned controls (B), and glycine-treated (G). Groups B and G were given a 30% total body surface area full-thickness burn. Group G was administered 1.5g/(kgd) glycine and group B was given the same dose of alanine via intragastric administration for 3d. Serum creatine kinase (CK), lactate dehydrogenase (LDH), aspartate transaminase (AST), and blood lactate, as well as myocardial ATP and glutathione (GSH) content, were measured. Cardiac contractile function and histopathological changes were analyzed at 12, 24, 48, and 72 hours. ResultsSerum CK, LDH, AST, and blood lactate increased, while myocardial ATP and GSH content decreased in both burned groups. Compared with group B, the levels of CK, LDH, and AST significantly decreased, whereas blood lactate as well as myocardial ATP and GSH content increased in group G. Moreover, cardiac contractile function inhibition and myocardial histopathological damage in group G significantly decreased compared with group B. ConclusionMyocardial histological structure and function were damaged significantly after burn. Glycine is beneficial to myocardial preservation by improving cardiomyocyte energy metabolism and increasing ATP and GSH abundance.

Mitochondrial energy metabolism plays a critical role in the cardioprotection afforded by intermittent hypobaric hypoxia

Intermittent hypobaric hypoxia (IHH) is an effective protective strategy against myocardial ischaemia-reperfusion (I/R) injury, but the precise mechanisms are far from clear. To understand the overall effects of IHH on the myocardial proteins during I/R, we analysed functional performance and the protein expression profile in isolated hearts from normoxic rats and from rats adapted to IHH (5000 m, 4 h day(-1), 4 weeks) following I/R injury (30 min/45 min). Intermittent hypobaric hypoxia significantly improved the postischaemic recovery of left ventricular function compared with the recovery in time-matched normoxic control hearts. Two-dimensional electrophoresis with matrix-assisted laser desorption/ionization and time-of-flight mass spectrometric analysis was then used to assess protein alterations in left ventricles from normoxic and IHH groups, with or without I/R. The expressions of 16 proteins changed by over fivefold; nine of these proteins are involved in energy metabolism. Immunoblot and real-time PCR analysis confirmed the IHH-increased expressions of the ATP synthase subunit β, mitochondrial aldehyde dehydrogenase and heat shock protein 27 in left ventricles. Furthermore, IHH significantly attenuated the reduction of myocardial ATP content, mitochondrial ATP synthase activity, membrane potential and respiratory control ratios due to I/R. In addition, inhibition of mitochondrial ATP synthase by oligomycin (1 μmol l(-1)) abolished the IHH-induced improvements in three parameters: postischaemic recovery of left ventricular function, mitochondrial membrane potential and respiratory control ratios. These results suggest that an improvement in mitochondrial energy metabolism makes an important contribution to the cardioprotection afforded by IHH against postischaemic myocardial dysfunction.

Abstract 9981: Systolic Heart Failure is Associated with Decreased Mitochondrial Respiration in Biopsies From Human Left Ventricle

Heart failure (HF) with left ventricular systolic dysfunction (LVSD) is associated with a shift in substrate utilization (metabolic remodeling) and reduced ATP and phosphocreatine (PCr) content. We hypothesized that these changes could be caused by reduced mitochondrial oxidative phosphorylation (OXPHOS) and reduced mitochondrial creatine kinase (miCK) capacity. Myocardial biopsies were obtained from left ventricle of patients undergoing cardiac valve- and left ventricular assist device (LVAD), surgery. The patients were stratified in two groups according to left ventricular ejection fraction (LVEF): Controls (LVEF= 55±2%, n=14) and LVSD (LVEF= 17±3%, n=12). Mitochondrial respiration was measured in permeabilized muscle fibers during successive additions of Krebs cycle substrates. In a separate experiment we assessed the oxidation of octanoyl-L-carnitine, a medium chain fatty-acid (MCFA). The kinetics of miCK was determined from APD titrations in the presence or absence of creatine, revealing the in situ enzyme capacity (Vmax) and sensitivity (C50). Octanoyl-L-carnitine elicited 41 % lower respiration in LVSD than in controls (10±2 vs. 17±2 ρmol sec -1 mg -1 , respectively, figure 1, P <0.05), whereas the sensitivity (C50) for octanoyl-L-carnitine was the same in both groups. Maximal respiratory capacity with dual electron input through complex I and II (malate, glutamate, succinate) was lower in the LVSD group compared with controls (76±8 vs. 104 ±7 pmol sec -1 mg -1 , respectively, P <0.05). Addition of creatine increased ADP sensitivity significantly in both groups (62 % vs 42 % reduction C50 respectively, P <0.05), but revealed no significant differences in Vmax. The novel finding of this study is that human LVSD is associated with a markedly diminished OXPHOS capacity, particularly in the oxidation of MCFA. This offers a candidate mechanism for decreased reliance on fatty-acid utilization in HF and for decreased myocardial ATP and PCr content.

Protective effects of therapeutic hypothermia in post-resuscitation myocardium

Aim of the studyPost-resuscitation therapeutic hypothermia has been recommended because of its neuroprotective effects. However, a few studies have reported the effects of therapeutic hypothermia on the heart, especially in ventricular fibrillation cardiac arrest. The aim of this study was to determine whether therapeutic hypothermia attenuates post-resuscitation myocardial injury in a swine cardiac arrest model. MethodsA prospective animal study was performed in the university hospital animal research laboratory. Ventricular fibrillation cardiac arrest was induced in domestic pigs weighing 35–40kg. After 6min of no flow time, cardiopulmonary resuscitation was provided to pigs, and the restoration of spontaneous circulation (ROSC) was achieved. The subjects were randomly allocated to a normothermic (NT group, n=5) or hypothermic (HT group, n=5) group. In the HT group, therapeutic hypothermia (core temperature 32–34°C) was maintained for 24h, and rewarming was performed over a period of 8h. In the NT group, core temperature was maintained at 37°C throughout the experiments. Sixty hours after ROSC, blood and myocardial tissues were harvested. ResultsSerum troponin I was not significantly different between the groups. However, myocardial histological damage was attenuated in the HT group. Myocardial ATP contents were higher in the HT group than in the NT group. Immunohistochemistry for apoptosis-related protein showed that survivin expression was higher in the HT group, and XAF1 and cleaved caspase-3 expressions were lower in the HT group than in the NT group. ConclusionsTherapeutic hypothermia attenuated histological myocardial injury in ventricular fibrillation cardiac arrest model of pigs while preserving more ATP and decreased apoptosis.

Seamless networks of myocardial bioenergetics

Seamless networks of myocardial bioenergetics

Autophagy limits acute myocardial infarction induced by permanent coronary artery occlusion

Ischemia is known to potently stimulate autophagy in the heart, which may contribute to cardiomyocyte survival. In vitro, transfection with small interfering RNAs targeting Atg5 or Lamp-2 (an autophagy-related gene necessary, respectively, for the initiation and digestion step of autophagy), which specifically inhibited autophagy, diminished survival among cultured cardiomyocytes subjected to anoxia and significantly reduced their ATP content, confirming an autophagy-mediated protective effect against anoxia. We next examined the dynamics of cardiomyocyte autophagy and the effects of manipulating autophagy during acute myocardial infarction in vivo. Myocardial infarction was induced by permanent ligation of the left coronary artery in green fluorescent protein-microtubule-associated protein 1 light chain 3 (GFP-LC3) transgenic mice in which GFP-LC3 aggregates to be visible in the cytoplasm when autophagy is activated. Autophagy was rapidly (within 30 min after coronary ligation) activated in cardiomyocytes, and autophagic activity was particularly strong in salvaged cardiomyocytes bordering the infarcted area. Treatment with bafilomycin A1, an autophagy inhibitor, significantly increased infarct size (31% expansion) 24 h postinfarction. Interestingly, acute infarct size was significantly reduced (23% reduction) in starved mice showing prominent autophagy before infarction. Treatment with bafilomycin A1 reduced postinfarction myocardial ATP content, whereas starvation increased myocardial levels of amino acids and ATP, and the combined effects of bafilomycin A1 and starvation on acute infarct size offset one another. The present findings suggest that autophagy is an innate and potent process that protects cardiomyocytes from ischemic death during acute myocardial infarction.

Effect of STH-2 cardioplegic solution containing levosimendan on ischemia-reperfusion injury in isolated rat hearts

Objective To investigate the effect of STH-2 cardioplegic solution containing levosimendan on ischemia-reperfusion (I/R) injury in isolated rat hearts. Methods Thirty-two male Wistar rats weighing 250-300 gwere anesthetized with intraperitoneal 3% pentobarbital 30 mg/kg. The hearts were rapidly excised and perfused with oxygenated (95% O2-5% CO2) K-H solution for 30 min in a Langendorff apparatus and then divided into 4groups (n = 8 each) according to the composition of cardioplegic solution: group Ⅰ control (group C) was perfused with STH-2 cardioplegic solution; group Ⅱ , Ⅲ and Ⅳ were peffused with STH-2 cardioplegic solution containing levosimendan 0.03 μmol/L (L1), 0.3 μmol/L (L2) and levosimendan 0.3 μmol/L + glibenclamide 10 μmol/L (L2+ G) respectively. The isolated hearts were first perfused with different cardioplegic solutions for 2 h and then with K-H solution for 30 min. The coronary effluent was collected before ischemia (baseline) and at 10, 20 and 30 min of reperfusion for measurement of creatine kinase (CK) and lactate dehydrogenase (LDH)activities. Myocardial specimens were obtained from apex at 30 min of reperfusion for determination of myocardial ATP and MDA contents and SOD activity. Results Perfusion with STH-2 cardioplegic solution significantly increased CK and LDH activities and MDA content, and significantly decreased SOD activity. Levosinendan 0.03or 0.3 μmol/L significantly attenuated the cardioplegia-induced increase in LDH,CK and SOD activities and MDA content. The protective effects of levosimendan on myocardium against I/R injury were reversed by glibenclamide to some extent. Conclusion Levosimendan can protect myocardium from I/R injury in a dose-dependent manner by opening KATP channel. Key words: Pyridazines; Cardioplegic solutions; Myocardial reperfusion injury

Apelin-12 improves metabolic and functional recovery of rat heart after global ischemia

This work was designed to explore efficacy of apelin-12 (A-12) as a cardioprotective agent when given before ischemia or at reperfusion using the isolated working heart model. Hearts of male Wistar rats were subjected to 30-min stabilization period followed by 35-min global ischemia and 30-min reperfusion. A short-term infusion of Krebs-Henseleit buffer (KHB) con-taining A-12 (35, 70, 140, 280 or 560 ?M) was ap-plied prior to ischemia (A-12-I) or at onset of reperfusion (A-12-R). KHB infusion was used as control. A-12 infusions induced a dose-dependent increase in recovery of coronary flow, contractile and pump function during reperfu-sion, with the largest augmentation of these indices in the A-12-I group. Both A-12 groups exhibited a significant reduction of LV diastolic pressure rise during reperfusion compared with control. Enhanced functional recovery in the A-12-I group was combined with a decrease in LDH leakage in perfusate on early reperfusion (by 36% vs. control, p < 0.05). Preischemic infusion of 140 ?M A-12 markedly increased myocardial ATP content, enhanced preservation of the total adenine nucleotide pool and improved recovery of the energy charge in reperfused hearts. There was a trend towards increase in myocardial phosphocreatine by the end of re- perfusion in the A-12-I group; however this benefit did not reach statistical significance. At the end of reperfusion, myocardial lactate and lactate/pyruvate ratio were on average 5-fold lower in A-12-I treated hearts compared with control ones and did not differ significantly from the initial values. Therefore, improved cardiac dysfunction after I/R injury and less cell mem-brane damage induced by A-12 are associated with maintaining high energy phosphates, particularly ATP, in reperfused myocardium. Changes in energy metabolism may play a role in mechanisms of cardioprotection afforded by A-12 during I/R stress.

A subset of 26S proteasomes is activated at critically low ATP concentrations and contributes to myocardial injury during cold ischemia

Molecular mechanisms leading to myocardial injury during warm or cold ischemia are insufficiently understood. Although proteasomes are thought to contribute to myocardial ischemia–reperfusion injury, their roles during the ischemic period remain elusive. Because donor hearts are commonly exposed to prolonged global cold ischemia prior to cardiac transplantation, we evaluated the role and regulation of the proteasome during cold ischemic storage of rat hearts in context of the myocardial ATP content. When measured at the actual tissue ATP concentration, cardiac proteasome peptidase activity increased by 225% as ATP declined during cold ischemic storage of hearts in University of Wisconsin (UW) solution for up to 48 h. Addition of the specific proteasome inhibitor epoxomicin to the UW solution inhibited proteasome activity in the cardiac extracts, significantly reduced edema formation and preserved the ultrastructural integrity of the cardiomyocyte. Utilizing purified 20S/26S proteasome enzyme preparations, we demonstrate that this activation can be attributed to a subset of 26S proteasomes which are stable at ATP concentrations far below physiological levels, that ATP negatively regulates its activity and that maximal activation occurs at ATP concentrations in the low μmol/L range. These data suggest that proteasome activation is a pathophysiologically relevant mechanism of cold ischemic myocardial injury. A subset of 26S proteasomes appears to be a cell-destructive protease that is activated as ATP levels decline. Proteasome inhibition during cold ischemia preserves the ultrastructural integrity of the cardiomyocyte.

Functional Significance and Morphological Characterization of Starvation-Induced Autophagy in the Adult Heart

To examine the functional significance and morphological characteristics of starvation-induced autophagy in the adult heart, we made green fluorescent protein-microtubule-associated protein 1-light chain 3 (LC3) transgenic mice starve for up to 3 days. Electron microscopy revealed round, homogenous, electron-dense lipid droplet-like vacuoles that initially appeared in cardiomyocytes as early as 12 hours after starvation; these vacuoles were identified as lysosomes based on cathepsin D-immunopositive reactivity and acid phosphatase activity. The increase in the number of lysosomes depended on the starvation interval; typical autophagolysosomes with intracellular organelles also appeared, and their numbers increased at the later phases of starvation. Myocardial expression of autophagy-related proteins, LC3-II, cathepsin D, and ubiquitin, increased, whereas both myocardial ATP content and starvation integral decreased. Treatment with bafilomycin A1, an autophagy inhibitor, did not affect cardiac function in normally fed mice but significantly depressed cardiac function and caused significant left ventricular dilatation in mice starved for 3 days. The cardiomyocytes were occupied with markedly accumulated lysosomes in starved mice treated with bafilomycin A1, and both the myocardial amino acid content, which was increased during starvation, and the myocardial ATP content were severely decreased, potentially contributing to cardiac dysfunction. The present findings suggest a critical role of autophagy in the maintenance of cardiac function during starvation in the adult.

ANESTHETIC PRECONDITIONING CONFERS ACUTE CARDIOPROTECTION VIA UP-REGULATION OF MANGANESE SUPEROXIDE DISMUTASE AND PRESERVATION OF MITOCHONDRIAL RESPIRATORY ENZYME ACTIVITY

The cellular and molecular mechanisms that underlie cardioprotection against I/R by anesthetic-induced preconditioning (APC) require further elucidation. Using isoflurane as a representative anesthetic, we evaluated the hypothesis that APC induces myocardial protection against I/R by attenuation of excessive reactive oxygen species and restoration of mitochondrial bioenergetics through postischemic up-regulation of manganese superoxide dismutase (MnSOD) expression and preservation of respiratory enzyme activity. Pentobarbital anesthetized open-chest Sprague-Dawley rats were subject to 30-min left coronary artery occlusion, followed by 120-min reperfusion. Before ischemia, rats were randomly assigned to receive 0.9% saline, two cycles of brief coronary artery occlusion and reperfusion, or a 30-min exposure to 1.0 minimum alveolar concentration isoflurane in the absence or presence of a specific mitochondrial adenosine triphosphate-sensitive potassium (KATP) channel blocker, 5-hydroxydecanoate; a membrane-permeable superoxide scavenger, 4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl; or a NOS inhibitor, N(G)-nitro-L-arginine methyl ester. Isoflurane exposure induced an initial increase in myocardial superoxide (O2-), but not NO level. It also significantly decreased infarct size and restored mitochondrial respiratory enzyme activity or ATP production in I/R rat hearts, along with suppression of the O2- surge at reperfusion and increase in MnSOD expression or enzyme activity. These protective effects were abrogated by 5-hydroxydecanoate or 4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl, but not by N(G)-nitro-L-arginine methyl ester pretreatment. These results suggest that opening of mitochondrial KATP channel, followed by O2- signaling, induces postischemic augmentation of MnSOD and preservation of mitochondrial respiratory enzyme activities, leading to attenuated cardiac O2- surge and restored ATP production during reperfusion, and underlie APC-induced cardioprotection.

Hibernating Myocardium

See related article, pages 103–112 Winter hibernation carries the promise of rejuvenation in the spring. In a similar fashion, myocardial “hibernation” describes a clinical phenomenon in which patients with ischemic left ventricular dysfunction demonstrate improved cardiac function following bypass surgery.1 The signature of myocardial hibernation is decreased blood flow with preserved glucose uptake, as demonstrated by positron emission tomography imaging, and identifies individuals with ischemic cardiomyopathy who may benefit from revascularization.2 In experimental models of hibernating myocardium, oxygen consumption is reduced in the absence of active ischemia.3,4 This implies that hibernation is a coordinated response to balance myocardial energy utilization with energy production capacity.5 However, within hibernating myocardium, several morphological and functional changes have been observed that can identify regions in which complete revascularization may not result in normalization of contraction.6–10 In fact, those myocardial regions with the greatest metabolic abnormalities in the hibernating tissue demonstrate the longest delay in recovery.11 In the current issue, Page et al12 demonstrate that the process of hibernation is associated with altered expression of mitochondrial proteins. Using 2D differential-in-gel electrophoresis and matrix-assisted laser desorption ionization time-of-flight mass spectrometry in a swine model of hibernation, they have found that key mitochondrial proteins associated with the electron transport chain are reduced. The functional importance of the decreased protein expression is documented by reduced activity measurements of the pyruvate dehydrogenase complex, cytochrome c oxidase, and citrate synthase. The parallel reductions in mitochondrial proteins and contractile function 5 months after placement of the coronary artery constrictor suggest that the “downregulation” of electron transport proteins is related to the reduced oxygen consumption. In fact, the reductions in ATPase correlate with the reduction in subendocardial blood flows in the hibernating myocardium. In addition, “upregulation” of several cytosolic proteins has been observed, including …

Possible Role of Hydrogen Sulfide on the Preservation of Donor Rat Hearts

Objective The aim of this study was to observe the preservative effect of hydrogen sulfide (H 2S) on donor rat hearts. Materials and Methods The hearts of 24 Sprague-Dawley rats were perfused on a Langendorff perfusion column for 30 minutes. We calculated and recorded the left ventricular-developed pressure (LVDP), and positive and negative derivatives of left ventricular systolic pressure (LVSP; +dP/dt and −dP/dt). Hearts were then arrested and stored for 6 hours at 4°C: group 1, Krebs-Henseleit (KH) solution; group 2, KH solution with 1 μmol/L NaHS; group 3, KH solution with 1 μmol/L NaHS and 10 μmol/L glibenclamide; group 4, St. Thomas II solution. Hearts were transferred back to the Langendorff column. After stabilizing for 30 minutes, LV performance was assessed as before. The donor hearts were kept for pathological study including myocardial water ratio, ATP content, and myocyte apoptosis index. Results The recovery rates of +dp/dtmax, −dp/dtmax, and LVDP of groups 2 and 4 were much better than those of groups 1 and 3. The hearts contracted immediately after reperfusion in group 4. Ventricular fibrillation was seen before contraction in the other 3 groups, with the longest duration in group. No significant difference in myocardial water ratio was found. The ATP content was the highest in group 2. Apoptosis was observed in the 4 groups with the lowest apoptosis index in group 2. Conclusions H 2S has a protective effect on rat donor hearts at the concentration of 1 μmol/L. The protective effect is better than that of St. Thomas II solution. The protective effect of H 2S can be blocked by glibenclamide.

Abstract 867: The Longevity Factor Sirt1 Exacerbates LV Dysfunction and Energy Depletion in Response to Pressure Overload

Sirt1, a class III histone deacetylase, extends the lifespan of many organisms. Longevity mechanisms usually confer stress resistance to organisms, and accumulation of stress resistance leads to lifespan extension. We have shown previously that Sirt1 is upregulated by stress up to 10 fold in the heart, and heart specific overexpression (up to 7.5 fold) of Sirt1 in mice not only suppresses histological/biochemical markers of aging, but also induces resistance to oxidative stress in the heart. We examined whether Sirt1 is protective against another pathologically relevant stimulus, namely pressure overload. Cardiac specific Sirt1 transgenic mice (Tg-Sirt1) from line #40, the line which has been shown to be protected against aging and oxidative stress, were subjected to transverse aortic constriction (TAC). Unexpectedly, at 10 days, the left ventricular (LV) ejection fraction (EF) in Tg-Sirt1 was significantly reduced (46 vs 71%, p&lt;0.01), the LV end diastolic dimension was significantly increased (4.1 vs 3.4 mm, p&lt;0.05), and the pressure gradient was reduced (92 vs 57 mmHg, p&lt;0.05), possibly due to reduced LV contractility, in Tg-Sirt1 compared with non-transgenic (NTg) controls. At 4 weeks, LV weight/body weight (BW) (6.4 vs 4.7, p&lt;0.05) and lung weight/BW (18.8 vs 7.0, p&lt;0.05) were significantly increased in Tg-Sirt1, LV +dP/dt was significantly reduced (4617 vs 7513, p&lt;0.05), and the LV end diastolic pressure was significantly elevated (13.6 vs 1.4 mmHg, p&lt;0.05) in Tg-Sirt1 compared with NTg. These results suggest that Tg-Sirt1 mice develop more severe LV dysfunction than NTg in response to TAC. Tg-Sirt1 mice exhibited significantly less apoptosis (−50%, p&lt;0.05) than NTg however, despite the development of LV dysfunction, suggesting that the LV dysfunction may be caused by apoptosis-independent mechanisms. The myocardial ATP content in Tg-Sirt1 was significantly less (−41%, p&lt;0.05) than that in NTg after TAC. These results suggest that the cardioprotective effect of Sirt1 depends on the type of stress: although modest expression of Sirt1 confers resistance to aging and oxidative stress, it exacerbates heart failure in response to TAC through apoptosis-independent mechanisms possibly involving energy depletion.

Invited commentary

Invited commentary

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.

Biochemical Studies on the Protective Effect of Betaine on Mitochondrial Function in Experimentally Induced Myocardial Infarction in Rats

The present study was designed to examine the cardioprotective effect of betaine on mitochondrial function in isoprenaline-induced myocardial infarction in rats with respect to changes in the mitochondrial energy status and antioxidant defense system. Prior oral treatment with betaine significantly prevented the isoprenaline-induced elevation in the levels of diagnostic maker enzymes [alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and creatine phosphokinase (CPK)] and homocysteine in plasma of the experimental group of rats. Its administration significantly counteracted the isoprenaline-induced aberrations in the myocardial energy status by maintaining the levels of myocardial ATP and betaine contents and the activities of mitochondrial TCA cycle enzymes [isocitrate dehydrogenase (ICDH), α-ketoglutarate dehydrogenase (α-KDH), succinate dehydrogenase (SDH), and malate dehydrogenase (MDH)] and respiratory marker enzymes (NADH dehydrogenase and cytochrome-c-oxidase) at near normalcy. It also exerted an antioxidant effect against isoprenalineinduced myocardial infarction by blocking the induction of mitochondrial lipid peroxidation (LPO). A tendency to minimize the isoprenaline-induced alterations in the level of reduced glutathione (GSH) and in the activities of glutathione-dependent antioxidant enzymes [glutathione peroxidase (GPx) and glutathione-S-transferase (GST)] and antiperoxidative enzymes [superoxide dismutase (SOD) and catalase (CAT)] in the heart mitochondria was also observed. The results of the present study indicate that the overall cardioprotective effect of betaine is probabl yr elated to its ability to maintain the myocardial energy status (ATP) at higher level by maintaining the activities of TCA cycle enzymes and respiratory marker enzymes at near normalcy, and/or to its free radical-scavenging ability against isoprenaline-induced lipid peroxidation, which is primarily responsible for the irreversible necrosis of the myocardial membrane.

Combined therapy with PPARα agonist and l-carnitine rescues lipotoxic cardiomyopathy due to systemic carnitine deficiency

Peroxisome proliferator-activated receptors (PPAR) are ligand-activated transcription factors that belong to the nuclear hormone receptor superfamily and are key regulators of fatty acid oxidation (FAO) in the heart. Systemic carnitine deficiency (SCD) causes disorders of FAO and induces hypertrophic cardiomyopathy with lipid accumulation. We hypothesized that activation of PPARalpha by fenofibrate, a PPARalpha agonist, in addition to conventional L-carnitine supplementation may exert beneficial effects on the lipotoxic cardiomyopathy in juvenile visceral steatosis (JVS) mouse, a murine model of SCD. Both wild-type (WT) and JVS mice were fed a normal chow, 0.2% fenofibrate containing chow (FE), a 0.1% L-carnitine containing chow (CA) or a 0.1% L-carnitine + 0.2% fenofibrate containing chow (CA + FE) from 4 weeks of age. Four to 8 animals per group were used for each experiment and 9 to 11 animals per group were used for survival analysis. At 8 weeks of age, JVS mice exhibited marked ventricular hypertrophy, which was more attenuated by CA + FE than by CA or FE alone. CA + FE markedly reduced the high plasma and myocardial triglyceride levels and increased the low myocardial ATP content to control levels in JVS mice. In JVS mice, myocardial 1,2-diacylglycerol (DAG) was significantly increased and showed a distinct fatty acid composition with elevation of 18:1(n-7,9) and 18:2(n-6) fatty acids compared with that in WT mice. CA + FE significantly altered the fatty acid composition of DAG and inhibited the membrane translocation of cardiac protein kinase C beta2 in JVS mice. Furthermore, CA + FE prevented the progressive left ventricular dysfunction and dramatically improved the survival rate in JVS mice (survival rate at 400 days after birth: 89 vs. 0%, P < 0.0001). PPARalpha activation, in addition to l-carnitine supplementation, may rescue the detrimental lipotoxic cardiomyopathy in SCD by improving cardiac energy and lipid metabolism as well as systemic lipid metabolism.