Efecto del ácido alfa lipoico sobre la peroxidación no enzimática en mitocondrias de corazón y cerebro de rata / Effect of alpha-lipoic acid against non-enzymatic peroxidation of rat heart and brain mitochondria

RESUMEN El ácido alfa lipoico (AAL) ha sido caracterizado como un antioxidante eficiente. Se ha propuesto como un agente terapéutico potencial en el tratamiento o prevención de diferentes alteraciones que pueden estar relacionadas con un desequilibrio del estado celular oxidoreductor. El objetivo de este trabajo fue analizar la sensibilidad a la peroxidación no enzimática (PNE) (ascorbato-Fe++ dependiente) en mitocondrias de corazón y cerebro de ratas incubadas con una solución de AAL. La PNE fue evaluada por el método de quimioluminiscencia (QL). Cuando se compararon las muestras control (sin el agregado del ascorbato-Fe++) con las muestras ascorbato-Fe++ dependientes, se observó un incremento significativo en la emisión lumínica. Simultáneamente, se incubaron las mitocondrias de ambos órganos con diferentes concentraciones de AAL (0,05, 0,15 y 0,25 mg/ml) observándose una protección diferencial. Las mitocondrias de cerebro de rata incubadas con dosis de 0,15 y 0,25 mg/ml de AAL fueron protegidas de los efectos de la PNE, mientras que, en las mitocondrias cardíacas, solo se observó protección con la dosis más alta de AAL (0,25 mg/ml). El análisis de QL indicó que las mitocondrias de cerebro fueron protegidas de manera más eficiente que las mitocondrias de corazón de rata. En este último caso, será necesario probar nuevas dosis de AAL para demostrar los efectos en estas membranas. En conclusión, AAL actuó como un antioxidante protector de las membranas de ambos órganos contra el daño peroxidativo.

ABSTRACT Alphalipoc acid (ALA) has been characterized as an efficient antioxidant. It has been proposed as a potential therapeutic agent in the treatment or prevention of different pathologies that may be related to an imbalance of the oxido reductive cell state. The objective of this work was to analyze the sensitivity to non-enzymatic peroxidation (NEP) (ascorbate-Fe++ dependent) in heart and brain mitochondria of rats incubated with an ALA solution. NEP was evaluated by the chemiluminescence method (CL). When the control samples (without the addition of ascorbate-Fe++) were compared with the ascorbate-Fe++ dependent samples, a significant increase in the light emission. Simultaneously, the mitochondria of both organs were incubated with different concentrations of ALA (0.05, 0,15 and 0,25 mg/ml), observing a differential protection. Rat brain mitochondria incubated with doses of 0.15 and 0,25 mg/ml of ALA were protected from the effects of NEP, while in cardiac mitochondria, protection was only observed with the highest dose of ALA (0,25 mg/ml). The CL analysis indicated that rat brain mitochondria were protected more efficiently than rat heart mitochondria. In the latter case, it will be necessary to test new doses of ALA to demonstrate the effects on these membranes. In conclusion, ALA acted as a protective antioxidant of the membranes of both organs against peroxidative damage.

Moderate-intensity exercise allows enhanced protection against oxidative stress-induced cardiac dysfunction in spontaneously hypertensive rats

The progression of myocardial injury secondary to hypertension is a complex process related to a series of physiological and molecular factors including oxidative stress. This study aimed to investigate whether moderate-intensity exercise (MIE) could improve cardiac function and oxidative stress in spontaneously hypertensive rats (SHRs). Eight-week-old male SHRs and age-matched male Wistar-Kyoto rats were randomly assigned to exercise training (treadmill running at a speed of 20 m/min for 1 h continuously) or kept sedentary for 16 weeks. Cardiac function was monitored by polygraph; cardiac mitochondrial structure was observed by scanning electron microscope; tissue free radical production was measured using dihydroethidium staining. Expression levels of SIRT3 and SOD2 protein were measured by western blot, and cardiac antioxidants were assessed by assay kits. MIE improved the cardiac function of SHRs by decreasing left ventricular systolic pressure (LVSP), and first derivation of LVP (+LVdP/dtmax and −LVdP/dtmax). In addition, exercise-induced beneficial effects in SHRs were mediated by decreasing damage to myocardial mitochondrial morphology, decreasing production of reactive oxygen species, increasing glutathione level, decreasing oxidized glutathione level, increasing expression of SIRT3/SOD2, and increasing activity of superoxide dismutase. Exercise training in SHRs improved cardiac function by inhibiting hypertension-induced myocardial mitochondrial damage and attenuating oxidative stresses, offering new insights into prevention and treatment of hypertension.

Salvianolic Acid A Protects Neonatal Cardiomyocytes Against Hypoxia/Reoxygenation-Induced Injury by Preserving Mitochondrial Function and Activating Akt/GSK-3β Signals / 中国结合医学杂志

OBJECTIVE@#To investigate the effects of salvianolic acid A (SAA) on cardiomyocyte apoptosis and mitochondrial dysfunction in response to hypoxia/reoxygenation (H/R) injury and to determine whether the Akt signaling pathway might play a role.@*METHODS@#An in vitro model of H/R injury was used to study outcomes on primary cultured neonatal rat cardiomyocytes. The cardiomyocytes were treated with 12.5, 25, 50 μg/mL SAA at the beginning of hypoxia and reoxygenation, respectively. Adenosine triphospate (ATP) and reactive oxygen species (ROS) levels were assayed. Cell apoptosis was evaluated by flow cytometry and the expression of cleaved-caspase 3, Bax and Bcl-2 were detected by Western blotting. The effects of SAA on mitochondrial dysfunction were examined by determining the mitochondrial membrane potential (△Ψm) and mitochondrial permeability transition pore (mPTP), followed by the phosphorylation of Akt (p-Akt) and GSK-3β (p-GSK-3β), which were measured by Western blotting.@*RESULTS@#SAA significantly preserved ATP levels and reduced ROS production. Importantly, SAA markedly reduced the number of apoptotic cells and decreased cleaved-caspase 3 expression levels, while also reducing the ratio of Bax/Bcl-2. Furthermore, SAA prevented the loss of △Ψm and inhibited the activation of mPTP. Western blotting experiments further revealed that SAA significantly increased the expression of p-Akt and p-GSK-3β, and the increase in p-GSK-3β expression was attenuated after inhibition of the Akt signaling pathway with LY294002.@*CONCLUSION@#SAA has a protective effect on cardiomyocyte H/R injury; the underlying mechanism may be related to the preservation of mitochondrial function and the activation of the Akt/GSK-3β signaling pathway.

Dual role of polyamines in heart ischemia/reperfusion injury through regulation of mitochondrial permeability transition pore / 生理学报

Polyamines (putrescine, spermidine, and spermine) are essential polycations that play important roles in various physiological and pathophysiological processes in mammalian cells. The study was to investigate their role in cardioprotection against ischemia/reperfusion (I/R) injury and the underlying mechanism. Isolated hearts from male Sprague-Dawley rats were Langendorff-perfused and cardiac I/R was achieved by 30 min of global ischemia followed by 120 min of reperfusion. Different concentrations of polyamines (0.1, 1, 10, and 15 μmol/L of putrescine, spermidine, and spermine), cyclosporin A (0.2 μmol/L), or atractyloside (20 μmol/L) were given 10 min before the onset of reperfusion. The hemodynamics were monitored; the lactate dehydrogenase (LDH) levels in the coronary effluent were measured spectrophotometrically; infarct size was determined by the 2,3,5-triphenyltetrazolium chloride staining method; and mitochondrial permeability transition pore (MPTP) opening was determined spectrophotometrically by the Ca-induced swelling of isolated cardiac mitochondria. The results showed that compared to I/R alone, 0.1 and 1 μmol/L polyamines treatment improved heart function, reduced LDH release, decreased infarct size, and these effects were inhibited by atractyloside (MPTP activator). In isolated mitochondria from normal rats, 0.1 and 1 μmol/L polyamines treatment inhibited MPTP opening. However, 10 and 15 μmol/L polyamines treatment had the opposite effects, and these effects were inhibited by cyclosporin A (MPTP inhibitor). Our findings showed that polyamines may have either protective or damaging effects on hearts suffering from I/R by inhibiting or activating MPTP opening.

Mitochondrial aldehyde dehydrogenase 2 protects against high glucose-induced injury in neonatal rat cardiomyocytes by regulating CaN-NFAT3 signaling pathway / 南方医科大学学报

OBJECTIVE@#To investigate whether CaN-NFAT3 pathway mediates the protective effects of aldehyde dehydrogenase (ALDH) 2 in high glucose-treated neonatal rat ventricular myocytes.@*METHODS@#The ventricular myocytes were isolated from the heart of neonatal (within 3 days) SD rats by enzyme digestion and cultured in the presence of 5-Brdu. After reaching confluence, the cultured ventricular myocytes were identified using immunofluorescence assay for -SA protein. The cells were then cultured in either normal (5 mmol/L) or high glucose (30 mmol/L) medium in the presence of ALDH2 agonist Alda-1, ALDH 2 inhibitor Daidzin, or Alda-1 and NFAT3 inhibitor (11R-VIVIT). Fluorescent probe and ELISA were used to detect intracellular Ca concentration and CaN content, respectively; ALDH2, CaN and NFAT3 protein expressions in the cells were detected using Western blotting.@*RESULTS@#Compared with cells cultured in normal glucose, the cells exposed to high glucose showed a significantly decreased expression of ALDH2 protein ( < 0.05) and increased expressions of CaN ( < 0.05) and NFAT3 proteins with also increased intracellular CaN and Ca concentrations ( < 0.01). Alda-1 treatment significantly lowered Ca concentration ( < 0.05), intracellular CaN content ( < 0.01), and CaN and NFAT3 protein expressions ( < 0.05), and increased ALDH2 protein expression ( < 0.05) in high glucose- exposed cells; Daidzin treatment significantly increased Ca concentration ( < 0.01) and intracellular CaN content ( < 0.05) in the exposed cells. Compared with Alda-1 alone, treatment of the high glucose-exposed cells with both Alda-1 and 11R-VIVIT did not produce significant changes in the expression of ALDH2 protein (>0.05) but significantly reduced the expression of NFAT3 protein ( < 0.05).@*CONCLUSIONS@#Mitochondrial ALDH2 protects neonatal rat cardiomyocytes against high glucose-induced injury possibly by negatively regulating Ca-CaN-NFAT3 signaling pathway.

Diabetes-Related Cardiac Dysfunction

The proposal that diabetes plays a role in the development of heart failure is supported by the increased risk associated with this disease, even after correcting for all other known risk factors. However, the precise mechanisms contributing to the condition referred to as diabetic cardiomyopathy have remained elusive, as does defining the disease itself. Decades of study have defined numerous potential factors that each contribute to disease susceptibility, progression, and severity. Many recent detailed reviews have been published on mechanisms involving insulin resistance, dysregulation of microRNAs, and increased reactive oxygen species, as well as causes including both modifiable and non-modifiable risk factors. As such, the focus of the current review is to highlight aspects of each of these topics and to provide specific examples of recent advances in each area.

Mitochondrial Metabolic Inhibition and Cardioprotection

No abstract available.

Correlation between uncoupling protein 2 expression and myocardial mitochondrial injury in rats with sepsis induced by lipopolysaccharide / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To investigate the correlation between uncoupling protein 2 (UCP2) expression and myocardial mitochondria injury in rats with sepsis induced by lipopolysaccharide (LPS).</p><p><b>METHODS</b>The rat model of sepsis was established through an intraperitoneal injection of LPS. Forty male Sprague-Dawley rats were randomly and equally divided into control group (an intraperitoneal injection of normal saline), sepsis 6 h group (LPS-6 h group), sepsis 12 h group (LPS-12 h group), sepsis 24 h group (LPS-24 h group), and sepsis 48 h group (LPS-48 h group). The serum and heart tissues were harvested at corresponding time points and myocardial mitochondria was extracted. The microplate reader was applied to measure creatine kinase (CK), creatine kinase-MB (CK-MB), and reactive oxygen species (ROS). Flow cytometry was applied to measure the degree of mitochondrial swelling and mitochondrial membrane potential (MMP). Western blot was used to measure the expression level of UCP2. Electron microscopy was applied to observe the morphological changes in heart tissues and myocardial mitochondria.</p><p><b>RESULTS</b>Compared with the control group, the LPS groups had significantly increased serum levels of CK, CK-MB, and myocardial ROS, as well as a significantly increased degree of mitochondrial swelling (P<0.05), and these values reached their peaks at 24 hours after LPS injection. The LPS groups had a significant decrease in MMP (P<0.05), which reached the lowest level at 24 hours after LPS injection. Western blot showed that the LPS groups had a significant increase in the expression level of myocardial UCP2 compared with the control group (P<0.05), which reached its peak at 24 hours after LPS injection. The results of electron microscopy showed mitochondrial swelling, partial rupture of the mitochondrial membrane, and cavity formation in rats in the LPS groups. The most severe lesions occurred in the LPS-24 h group. In rats with LPS, the ROS level in the myocardial mitochondria and the degree of mitochondrial swelling were positively correlated with the expression level of UCP2 (r=0.796 and 0.893, respectively; P<0.05), while MMP was negatively correlated with the expression level of UCP2 (r=-0.903, P<0.05).</p><p><b>CONCLUSIONS</b>In the rat model of sepsis, the myocardium and myocardial mitochondria have obvious injuries, and the expression level of UCP2 is closely correlated with mitochondrial injury. Therefore, UCP2 might play an important role in myocardial mitochondrial injury in sepsis.</p>

Dyslipidemia in young patients with type 1 diabetes mellitus

Objective The association between type 1 diabetes mellitus (T1D) and dyslipidemia (DLP) increases the risk of cardiovascular disease (CVD). The aim of this study was to evaluate the presence of dyslipidemia in young T1D patients.Materials and methods The study design was cross-sectional and descriptive. We reviewed medical records of T1D patients followed at an endocrinology service, from 1998-2012. Data collected: gender, actual age and age at diagnosis, duration of T1D since diagnosis, body mass index (BMI), pubertal stage, glycemic control (GC) determined by glycated hemoglobin (HbA1c), total cholesterol (TC), HDL, LDL, triglycerides (TG). To analyze lipid profile and metabolic control, we used the Brazilian Society of Diabetes Guidelines.Results Were included 239 T1D patients, 136 (56.9%) females; mean ± SD: actual age 15.7 ± 5.0 years and at T1D diagnosis 7.3 ± 3.9; T1D duration 10.6 ± 6.4 years, 86.6% puberty, 15.1% overweight. The prevalence of DLP was 72.5%, 63.3% females, 86.6% puberty, mean ± SD: actual age 15.4 ± 4.8 years and at T1D diagnosis 7.2 ± 4.1 years, duration of T1D 10.7 ± 6.1 years. We found high-CT in 56.7%, low-HDL = 21.7%, high LDL = 44.0%, high-TG = 11.8%. Between females with DLP, 83.5% was in puberty. We find correlation between the presence of DLP, a poor GC and BMC.Conclusion We found a high prevalence of DLP in young patients with T1D, particularly in puberty females. Programs targeting the prevention of dyslipidemia should be adopted, especially for this group, in order to prevent/delay chronic complications and cardiovascular disease. Arch Endocrinol Metab. 2015;59(3):215-9.

Protective Effects of Cornus Officinalis Total Glycosides and Cornus Polysaccharides on Myocardial Mitochondria of Acute Myocardial Infarction Rats: an Experimental Study / 中国中西医结合杂志

<p><b>OBJECTIVE</b>To observe the effect of Cornus Officinalis total glycosides (COTG) and Cornus polysaccharides (CP) on myocardial mitochondria and expression levels of glycogen synthase kinase-3β (GSK-3β) of acute myocardial infarction (AMI) rats.</p><p><b>METHODS</b>The AMI rat model was established by ligating the left anterior descending branch of coronary artery. Rats were divided into 5 groups according to random digit table, i.e., the sham-operation group, the model group, the COTG prevention group, the CP treatment group, the COTG treatment group, 12 in each group. Normal saline was administered to rats in the normal control group and the model group by gastrogavage. Corresponding medication was respectively administered to rats in the rest 3 groups by gastrogavage. The cardiac function was detected by echocardiography and hemodynamics. The infarct size was determined by Masson trichrome staining. The expression of mitochondrial biogenesis genes such as a subunit of peroxisome proliferators-activated receptor-γ coactivator-1 (PGC-1α), PGC-1β, nuclear respiratory factor-1 (NRF-1), and GSK-3P mRNA were detected by Real-time PCR.</p><p><b>RESULTS</b>Compared with the sham-operation group, the myocardial infarction size increased, cardiac function decreased, the expression of PGC-1α, PGC-1β, and NRF-1 mRNA decreased, and the expression of GSK-3β mRNA increased (all P <0. 05). Compared with the model group, myocardial infarction sizes were reduced, cardiac function was improved, the expression of NRF-1 mRNA was elevated in the COTG prevention group, the CP treatment group, the COTG treatment group; the expression of the PGC-1α and PGC-1β mRNA was elevated in the COTG prevention group and the CP treatment group; the expression of GSK-3β mRNA was reduced in the CP treatment group (all P <0. 05). Compared with the CP prevention group, fractional shortening (FS) and aortic systolic blood pressure (SBP) increased in the CP treatment group; ejection fraction (EF) decreased in the CP treatment group; the expression of PGC-1α, PGC-1β, NRF-1 mRNA were reduced in the the CP treatment group and the COTG treatment group; the expression of GSK-3β mRNA decreased in the CP treatment group (all P <0. 05). Compared with the COTG treatment group, FS, EF, left ventricular end systolic pressure (LVESP), SBP, and the expression of GSK-3β mRNA were reduced in the CP treatment group (P <0. 05).</p><p><b>CONCLUSIONS</b>COTG and CP could improve cardiac function, reduce the myocardial infarction area, and promote biogenesis of myocardial mitochondria. Their protective effects on the mitochondria of cadiocytes might be achieved by GSK-3β signalina pathway.</p>

Effects of exercise training on myocardial mitochondrial miR-499-CaN-Drp-1 apoptotic pathway in mice / 中国应用生理学杂志

<p><b>OBJECTIVE</b>To detect the levels of miR-499 and relative proteins in hearts of mice after exercise training, and investigate the mechanism of exercise-regulative apoptosis.</p><p><b>METHODS</b>Male C57BL/6 mice were randomly divided into 3 groups( n = 14): sedentary (SE), exercise training 1 (ET1) and exercise training 2 (ET2) group. SE did not do any exercise. ET1 performed swimming training for 8 weeks. ET2 performed the same work as ET1 until the 5th week. Then, mice trained twice a day until the end of training. TUNEL assay was applied to test myocardial apoptosis, RT-PCR and Western blot were used to detect miR-499 and proteins levels respectively.</p><p><b>RESULTS</b>Compared with SE, stress in ET1 failed to affect apoptotic index (AI) and miR-499-CaN-Drp-1 pathway (P > 0.05). In contrast, exercise load in ET2 increased miR-499 level, decreased Drp-1 level and AI with statistical significance respectively (P < 0.05), but neither CaN expression nor CaN activity was changed significantly (P > 0.05).</p><p><b>CONCLUSION</b>Swimming training can inhibit myocardial apoptosis, and the decrease in Drp-l may be responsible for the reduced myocardial apoptosis. CaN, the upstream protein, does not participate in exercise-regulative apoptosis.</p>

Effects of microtubule depolymerization on spontaneous beating and action potential of cardiac myocytes in rats and its mechanism / 中华烧伤杂志

<p><b>OBJECTIVE</b>To explore the effects of microtubule depolymerization (MD) on the spontaneous beating rate, action potential (AP), and oxygen consumption of cardiac myocytes in rats and its mechanism.</p><p><b>METHODS</b>One-hundred and eighty neonatal SD rats divided into 12 batches were used in the experiment, and 15 rats in each batch were sacrificed for the isolation and culture of cardiac myocytes after the heart tissues were harvested. The cardiac myocytes were respectively inoculated in one 12-well plate filled with 6 round cover slips, one 12-well plate filled with 6 square cover slips, two cell culture flasks, and two cell culture dishes. After routine culture for three days, the cardiac myocytes from all the containers were divided into normal control group (NC, routinely cultured with 3 mL DMEM/F12 solution rewarmed at 37 °C for 3 h) and group MD (routinely cultured with 3 mL DMEM/F12 solution rewarmed at 37 ° and containing 8 µmol/L colchicine for 3 h) according to the random number table, with 3 holes, 1 flask, or 1 dish in each group. The morphological changes in microtubules were observed with confocal laser scanning microscope after immunofluorescent staining. The content of polymerized or dissociative α-tubulin was determined by Western blotting. Spontaneous beating rate of the cells was observed and calculated under inverted microscope. Dissolved oxygen concentration of DMEM/F12 solution containing cardiac myocytes was determined by oxygen microelectrode system before and after the addition of colchicine. Additionally, dissolved oxygen concentration of DMEM/F12 solution and colchicine + DMEM/F12 solution was determined. The whole-cell patch-clamp technique was used to record AP, delayed rectifier K+ current (I(K)), and L-type Ca2+ current (I(Ca-L)) in cardiac myocytes; current density-voltage (I-V) curves were drawn based on the traces. Data were processed with independent or paired samples t-test.</p><p><b>RESULTS</b>(1) In group NC, microtubules of cardiac myocytes were around the nucleus in radial distribution with intact and clear linear tubiform structure. The microtubules in group MD were observed in dispersive distribution with damaged structure and rough linear tubiform structure. (2) In group MD, the content of dissociative α-tubulin of cells (0.61 ± 0.03) was obviously higher than that in group NC (0.46 ± 0.03, t = -6.99, P < 0.05), while the content of polymerized α-tubulin (0.57 ± 0.04) was significantly lower than that in group NC (0.88 ± 0.04, t = 9.09, P < 0.05). (3) Spontaneous beating rate of cells was (59 ± 8) times per min in group MD, which was distinctly higher than that in group NC [(41 ± 7) times per min, t = 5.62, P < 0.01]. (4) Dissolved oxygen concentration of DMEM/F12 solution containing cardiac myocytes was (138.4 ± 2.5) µmol/L, and it was reduced to (121.7 ± 3.6) µmol/L after the addition of colchicine ( t = 26.31, P < 0.05). There was no obvious difference in dissolved oxygen concentration between DMEM/F12 solution and colchicine + DMEM/F12 solution (t = 0.72, P > 0.05). (5) Compared with that of group NC, AP morphology of cells in group MD changed significantly, with unobvious repolarization plateau phase and shorter action potential duration (APD). The APD20, APD50, and APD90 were respectively (36.2 ± 3.8), (73.7 ± 5.7), and (115.1 ± 8.0) ms in group MD, which were significantly shorter than those of group NC [(40.2 ± 2.3), (121.4 ± 7.0), and (169.4 ± 5.6) ms, with t values respectively 2.61, 15.88, and 16.75, P values below 0.05]. (6) Compared with that of group NC, the I-V curve of I(K) of cells in group MD moved up with higher current density under each test voltage (0 to 40 mV) after activation ( with t values from 2. 70 to 3. 76, P values below 0.05) . (7) There was not much alteration in current density of I(Ca-L) under each test voltage (-30 to 50 mV) between 2 groups (with t values from -1.57 to 1.66, P values above 0.05), and their I-V curves were nearly overlapped.</p><p><b>CONCLUSIONS</b>After MD, the I(K) is enhanced without obvious change in I(Ca-L), making AP repolarization faster and APD shortened. Then the rapid spontaneous beating rate increases oxygen consumption of cardiac myocytes of rats.</p>

Association between clinical features and histopathological findings in patients with left ventricular non-compaction cardiomyopathy / 中华心血管病杂志

<p><b>OBJECTIVE</b>To investigate the association between clinical and histopathological features in patients with left ventricular non-compaction cardiomyopathy (LVNC).</p><p><b>METHODS</b>Histopathological examinations were made on 11 LVNC recipient hearts from June 2004 to June 2014 in Fuwai Hospital, myocardial ultrastructure changes were detected using transmission electron microscopy. Association between clinical and pathological features were analyzed.</p><p><b>RESULTS</b>Patients were (24 ± 11) years old. There were 6 patients with mucus matrix LVNC, 3 patients with fibrous fatty infiltration, and 2 patients with cardiomyocytes proliferation. The gross morphological changes of LVNC hearts were characterized by numerous and prominent trabeculations with deep intratrabecular recesses in left ventricular myocardium. Ratios of the thicker noncompacted endocardial layer (N) and thin epicardial compacted layer (C) (N/C ratio) were ≥ 2.0, and the most serious lesions were located in the left ventricular apex, and followed by the left ventricular free wall. Histological microscopic examinations evidenced numerous matrix-like material and immature cardiomyocytes on endocardial tissue. Transmission electron microscopy revealed mitochondrial abnormalities on morphology, number, and distribution, underdeveloped cardiomyocytes and anomalies of intercalated disc structure, increased deposition of extracellular matrix-like substance and perinuclear glycogen. Pathological changes on cytoplasmic matrix and intercalated disc were present in all three tissue types of LVNC in this cohort and mitochondria hyperplasia was detected in patients with fibrous fatty infiltration. Heart weight ≥ 350 g is often associated with increased number of mitochondria. Increased cytoplasmic matrix was often detected in patients with LVEF ≥ 30% while intercalated disc anomalies were often detected in patients with LVEF < 30%.</p><p><b>CONCLUSION</b>Histological changes were closely related clinical features in patients with LVNC.</p>

Mitochondrial aldehyde dehydrogenase in myocardial ischemia-reperfusion injury: from bench to bedside / 生理学报

Acute myocardial infarction is one of the major causes of mortality worldwide. Reperfusion in a timely fashion is the most effective way to limit infarct size. However, reperfusion can itself prompt further myocardial injury. This phenomenon is commonly known as myocardial ischemia-reperfusion (IR) injury. Mitochondrial aldehyde dehydrogenase (ALDH2) is an enzyme metabolizing acetaldehyde and toxic aldehydes. Increasing evidence has revealed a cardioprotective role of ALDH2 in myocardial IR injury. Evidence from animal studies has shown that ALDH2 diminishes acute myocardial infarct size, ameliorates cardiac dysfunction and prevents reperfusion arrhythmias. The activity of ALDH2 is severely compromised if it is encoded by the mutant ALDH2*2 gene, with an incidence of approximately 40% in Asian populations. Epidemiological surveys in the Asian population have depicted that ALDH2 polymorphism is closely associated with higher prevalence of acute myocardial infarction and coronary artery disease. Therefore, targeting ALDH2 may represent a promising avenue to protect against IR injury. This review recapitulates the underlying mechanisms involved in the protective effect of ALDH2 in cardiac IR injury. Translational potential of ALDH2 in the management of coronary heart disease is also discussed.

Fiebre chikungunya en México: caso confirmado y apuntes para la respuesta epidemiológica / Chikungunya fever in Mexico: confirmed case and notes on the epidemiologic response

La fiebre chikungunya (CHIK) es una enfermedad viral transmitida al ser humano por el mismo vector del dengue, el mosquito Aedes. Además de fiebre y fuertes dolores articulares, produce otros síntomas como mialgias, cefalea, náuseas, cansancio y exantema. No tiene tratamiento específico; el manejo terapéutico de los pacientes se enfoca en el alivio de los síntomas. Históricamente se han reportado brotes de grandes proporciones; incluso desde 2010 se llegó a considerar como una potencial epidemia emergente. En 2013 se introdujo a las islas del Caribe y recientemente se ha reportado en el continente americano. En este trabajo se describe el primer caso confirmado de chikungunya en México, en el municipio de Tlajomulco de Zúñiga, Jalisco, en mayo de 2014, importado de la isla Antigua y Barbuda, en el Caribe, por una mujer de 39 años de edad.

Chikungunya fever (CHIK) is a viral disease transmitted to human beings by the same vector as dengue -the Aedes mosquito. Besides fever and severe pain in the joints, it produces other symptoms such as myalgias, headache, nausea, fatigue and exanthema. There is no specific treatment for it; the therapeutic management of patients focuses on symptom relief. Historically, outbreaks of large proportions have been reported; even since 2010 it was considered to be a potential emerging epidemic. In 2013 it was introduced into the islands of the Caribbean, and it has recently been reported in the American continent. This paper describes the first confirmed case of chikungunya in Mexico -in the municipality of Tlajomulco de Zúñiga, Jalisco, in May, 2014-, which was imported from the Caribbean island of Antigua and Barbuda by a 39 year-old woman.

Importancia clínica del estudio estructural y funcional de las mitocondrias en las diferentes miocardiopatías / Clinical significance of structural and functional study of mitochondria in different cardiomyopathies

Los principales mecanismos que intervienen en la génesis y progresión de la insuficiencia cardiaca no se encuentran aclarados totalmente. El presente estudio se llevó a cabo para analizar la participación de las mitocondrias en la insuficiencia cardíaca y el posible paralelismo que hubiere entre el músculo cardíaco y el músculo esquelético en relación a los síntomas clínicos y el daño mitocondrial. También se analizaron los factores de riesgo para enfermedad cardiovascular en los diferentes grupos de estudio, y como se vinculan con las alteraciones estructurales y funcionales de las mitocondrias; así como se estudiaron en un modelo experimental, las posibles modificaciones de las mitocondrias cardíacas y esqueléticas producidas por los distintos fármacos utilizados para el tratamiento de la insuficiencia cardíaca.Veintisiete (27) pacientes que se sometieron a cirugía cardiovascular por diferentes razones y aceptaron participar en este estudio se incluyeron.Los criterios de inclusión para el grupo de control (n = 6) fueron pacientes de ambos sexos con fracción de eyección ventricular izquierda normal (FEVI) (> 60%), sin enfermedad reumatológica, diabetes, hipertensión arterial, dislipemia, obstrucción de vasos coronarios, siendo la comunicación interauricular el diagnóstico único para la cirugía.

Abstract: The fundamental mechanisms involved in the genesis and progression of heart failure are not clearly understood. Present study was conducted to analyze the cardiac mitochondrial involvement in heart failure, the possible parallelism between cardiac and skeletal muscle and if there is a link between clinical symptoms and mitochondrial damage. The risk factors were also analyzed in the different groups under study and the possible modification upon cardiac and skeletal mitochondria produced by the different drugs used for cardiac failure treatment was also studied in an experimental model. Twenty seven patients who underwent cardiovascular surgery for different reasons and accepted to participate in this study were included.

Effects of total flavones of Elsholtzia splendens in isolated ischemia/reperfusion rat hearts / 中国应用生理学杂志

<p><b>OBJECTIVE</b>To investigate the influence of total flavonoids of Elsholtzia splendens (TFES) on isolated ischemia/reperfusion rat hearts and its underlying mechanisms.</p><p><b>METHODS</b>Hearts isolated from male SD rats were perfused on the Langendorff apparatus and subjected to global ischemia for 30 min followed by 120 min of reperfusion. The cardiac infarct size was measured by TTC staining. Hemodynamic parameters and the level of lactate dehydrogenase (LDH) in the coronary effluent were measured. Absorbance at 520 nm was determined in isolated cardiac mitochondria exposed to 200 micromol/L CaCl2 to detect the opening of the mitochondrial permeability transition pore.</p><p><b>RESULTS</b>Pretreatment with TFES (1, 10, 100 microg/ml) for 5 min decreased infarct size and LDH release and improved the recovery of the left ventricular developed pressure. In mitochondria, the decrease of absorbance at 520 nm evoked by CaCl2 was greatly inhibited by TFES.</p><p><b>CONCLUSION</b>TFES prevents myocardial ischemia/reperfusion injury, and this cardioprotective effect is probably via inhibiting mitochondrial permeability transition pore opening.</p>

Estudo dos efeitos da radioterapia no tecido cardíaco e sua associação com o metabolismo energético / Study of the effects of radiation therapy in cardiac tissue and its association with energy metabolism

Durante o tratamento radioterápico para tumores localizados na região torácica, parte do coração frequentemente é incluída no campo de tratamento e pode receber doses de radiação ionizante, significativas em relação à terapêutica. A irradiação do coração é capaz de causar importantes complicações cardíacas ao paciente, caracterizadas por alterações funcionais progressivas cerca de 10 a 20 anos após a exposição do órgão. Devido ao seu alto grau de contração e grande consumo energético, o tecido cardíaco é altamente dependente do metabolismo oxidativo que ocorre nas mitocôndrias. Danos as estas organelas podem levar ao decréscimo da produção de energia, tendo um impacto direto sobre a performance cardíaca. Ainda, ao interagir com as células, a radiação ionizante pode gerar uma série de eventos bioquímicos que conduzem a uma resposta celular complexa, em que muitas proteínas parecem estar envolvidas. Tendo em vista tais conhecimentos, o objetivo do estudo foi avaliar o aspecto ultraestrutural do tecido cardíaco, a bioenergética mitocondrial e a expressão diferencial de proteínas após irradiação. Os ensaios foram realizados em amostras de tecido cardíaco de ratos Wistar irradiados com dose única de 20 Gy direcionada ao coração. As análise tiveram início 4 e 32 semanas após irradiação. A análise ultraestrutural foi realizada através de microscopia eletrônica de transmissão. A respiração mitocondrial foi mensurada em oxígrafo, a partir das taxas de consumo de oxigênio pelas fibras cardíacas. A identificação de proteínas diferencialmente expressas foi investigada através de duas técnicas proteômicas: 2D-DIGE (2-D Fluorescence Difference Gel Electrophoresis) e uma abordagem label-free seguida de espectrometria de massas. Os resultados mostraram que os efeitos tardios da radiação incluem a degeneração das mitocôndrias e das unidades contráteis do tecido cardíaco, disfunções na cadeia respiratória mitocondrial e expressão diferencial de proteínas...

During radiotherapy for tumors located at toracic region, part of the heart is often included in the treatment field and may receive a significant ionizing radiation dose comparing to the therapeutics. Heart irradiation is able to cause substantial cardiac complications to patient, characterized by functional progressive changes from 10 to 20 years after the exposure of the organ. Because of its high level of contraction and large energetic consumption, cardiac tissue is highly depending on oxidative metabolism which happens at mitochondrias. Damage to these organelles can lead to decreased energy production, having a direct impact on cardiac performance. Even when interacting with cells, ionizing radiation can generate a series of biochemical events that lead to a complex cellular response, in many proteins seem to be involved. Given this knowledge, the aim of the study was to evaluate the ultrastructural appearance of cardiac tissue, mitochondrial bioenergetics and differential expression of proteins after irradiation. The tests were performed on samples of cardiac tissue of rats irradiated with single dose of 20 Gy directed to the heart. The analysis started 4 to 32 weeks after irradiation. The ultrastructural analysis was performed by transmission electron microscopy. Mitochondrial respiration was measured in oxigraph from rates of oxygen consumption by cardiac fibers. The identification of differentially expressed proteins was investigated using two proteomic techniques: 2D-DIGE (2-D Fluorescence Difference Gel Electrophoresis) and a label-free approach followed by mass spectrometry. The results showed that the late effects of radiation include degeneration of mitochondria and contractile units of cardiac tissue, dysfunction in the mitochondrial respiratory chain and differential expression of proteins involved in energy metabolism of carbohydrates, lipids and phosphocreatine. In general, the study showed that the cardiac irradiation damages...

Role of mitochondrial damage during cardiac apoptosis in septic rats / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Myocardial apoptosis is involved in the pathogenesis of sepsis-related myocardial depression. However, the underlying mechanism remains unknown. This study investigated the role of mitochondrial damage and mitochondria-induced oxidative stress during cardiac apoptosis in septic rats.</p><p><b>METHODS</b>Seventy-two Sprague-Dawley rats were randomly divided into a control group and septic group receiving lipopolysaccharide injection. Heart tissue was removed and changes in cardiac morphology were observed by light microscopy and scanning electron microscopy. In situ apoptosis was examined using terminal transferase-mediated dUTP nick end-labeling assay and nuclear factor-kappa B activation in myocardium by Western blotting to estimate myocardial apoptosis. Appearance of mitochondrial cristae and activation of cytochrome C oxidase were used to evaluate mitochondrial damage. Oxidative stress was assessed by mitochondrial lipid and protein oxidation, and antioxidant defense was assessed by mitochondrial superoxide dismutase and glutathione peroxidase activity.</p><p><b>RESULTS</b>Sepsis-induced inflammatory cell infiltration, myocardium degeneration and dropsy were time-dependent. Expanded capillaries were observed in the hearts of infected rats 24 hours post-challenge. Compared with sham-treated rats, the percentage of cell apoptosis increased in a time-dependent manner in hearts from septic rats at 6 hours, 12 hours and 24 hours post-injection (P < 0.05). The expression of nuclear factor-kappa B p65 decreased gradually in the cytosol and increased in the nucleus during sepsis, indicating that septic challenge provoked the progressive activation of nuclear factor-kappa B. Mitochondrial cristae and activation of cytochrome C oxidase increased in a time-dependent manner. Both superoxide dismutase and glutathione peroxidase activities decreased, while mitochondrial lipid and protein oxidation increased between 6 and 24 hours after lipopolysaccharide challenge.</p><p><b>CONCLUSIONS</b>Septic challenge induced myocardial apoptosis and mitochondrial damage. Furthermore, mitochondrial damage via alteration of defenses against reactive oxygen species might play an important role in myocardial apoptosis during sepsis.</p>

Clinical, biochemical and genetic analysis of the mitochondrial disorders presenting with cardiac damage / 中华儿科杂志

<p><b>OBJECTIVE</b>Mitochondrial disease is a group of energy metabolic disorders, characterized by involvement of multisystem with high energy requirements. Encephalomyopathies are common clinical findings of the mitochondrial diseases. However, mitochondrial cardiac damage is not rare. In this study, the clinical, biological, and genetic analyses were performed in three patients with mitochondrial cardiac damage, in order to understand the characteristics of mitochondrial diseases.</p><p><b>METHOD</b>Three girls presented with arrhythmia and cardiac enlargement from the age of 3, 4 and 8 years respectively. They were admitted into the Peking University First Hospital. Infection, autoimmune diseases, aminoacidopathies, organic acidurias, mitochondrial-fatty acid oxidation defects, and lysosomal storage disease were excluded by routine laboratory examinations and metabolic analysis for blood amino acids, acylcarnitines, urinary organic acids, and lysosome activity assay. Peripheral leukocytes mitochondrial respiratory chain enzyme I to V activities were measured by spectrophotometry. The entire sequence of the mitochondrial DNA was analyzed.</p><p><b>RESULT</b>In two patients (case 1 and case 3), hypertrophic cardiomyopathy and grade I to grade II of cardiac function were found. One patient (case 2) was diagnosed with arrhythmia and grade I of cardiac function. Increased creatine phosphokinase and creatine kinase isoenzyme MB were observed. Mitochondrial respiratory chain complex deficiencies were indentified in the three patients. Patient 1 had combined deficiencies of complex III and V. The activity of complex I+III was 18.7 nmol/(min·mg mitochondrial protein) (control 84.4 ± 28.5). The activity of complex V was 20.4 nmol/(min·mg mitochondrial protein) (control 103.7 ± 29.2). In her mitochondrial gene, A14693G on tRNA(Glu) and T16519C on D-loop were found. Patient 2 had an isolated complex I deficiency. The activity was 22.0 nmol/(min·mg mitochondrial protein) (control 44.0 ± 5.4). A16183C, T16189C and G15043A mutations on D-loop were found. Patient 3 had a combined deficiency of complex IV and V. The activity of complex IV was 21.0 nmol/(min·mg mitochondrial protein) (control 54.1 ± 12.3). The activity of complex V was 23.2 nmol/(min·mg mitochondrial protein) (control 103.7 ± 29.2). C253T and C16187T mutations on D-loop were detected. Haplotype analysis showed that three patients belong to H2a2a. Improvement was observed after the treatment with L-carnitine, coenzyme Q10, vitamin C and E. At present, the patients are 7, 5 and 8 years old. Although excise intolerance still persists, they had a good general condition with normal school life.</p><p><b>CONCLUSION</b>The mitochondrial diseases with cardiac damage show cardiomyopathy, arrhythmia and exercise intolerance. Many kinds of mitochondrial respiratory chain deficiency were observed. A14693G in mitochondrial tRNA(Glu) gene is probably one of the causes in China.</p>