Stress In Cardiac Tissue Research Articles

Indole-3-acetic acid exposure leads to cardiovascular inflammation and fibrosis in chronic kidney disease rat model

Indole-3-acetic acid (IAA), a protein-bound uremic toxin, has been linked to cardiovascular morbidity and mortality in chronic kidney disease (CKD) patients. This study explores the influence of IAA (125 mg/kg) on cardiovascular changes in adenine sulfate-induced CKD rats. HPLC analysis revealed that IAA-exposed CKD rats had lower excretion and increased circulation of IAA compared to both CKD and IAA control groups. Moreover, echocardiography indicated that CKD rats exposed to IAA exhibited heart enlargement, thickening of the myocardium, and cardiac hypertrophy in contrast to CKD or IAA control group. Biochemical analyses supported the finding that IAA-induced CKD rats had elevated serum levels of c-Tn-I, CK-MB, and LDH; there was also evidence of oxidative stress in cardiac tissues, with a significant decrease in SOD and CAT levels, as well as an increase in MDA levels. The gene expression analysis found significant increases in ANP, BNP, β-MHC, TNF-α, IL-1β, and NF-κB levels in IAA-exposed CKD groups in contrast to the CKD or IAA control group. In addition, higher cardiac fibrosis markers, including Col-I and Col-III. The findings of this study indicate that IAA could trigger cardiovascular inflammation and fibrosis in CKD conditions.

Protective effects of mesenchymal stem cells-derived extracellular vesicles against ischemia-reperfusion injury of hearts donated after circulatory death: Preliminary study in a pig model

IntroductionInsufficient supply of cardiac grafts represents a severe obstacle in heart transplantation. Donation after Circulatory Death (DCD), in addition to conventional donation after brain death, is one promising option to overcome the organ shortage. However, DCD organs undergo an inevitable more extended period of warm unprotected ischemia between circulatory arrest and graft procurement. Mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) have shown remarkable protective effects against ischemia-reperfusion injury. Thus, we aimed to enhance grafts preservation from DCD donors, through treatment with MSC-EVs. MethodsFemale pigs were euthanized by barbiturate overdose and after 20 min of a flat EKG, the chest was opened, the heart harvested and subsequently connected to an extracorporeal perfusion machine. MSC-EVs, isolated by ion exchange chromatography, were added to the perfusion solution (1×1011 particles) and the heart was perfused for 2 h. Then, heart tissue biopsies were taken to assess histological changes, mitochondrial morphology, antioxidant enzyme activity and inflammation mediators’ expression. Biochemical parameters of myocardial viability were assessed in the perfusate. ResultsThe treatment with MSC-EVs significantly prevented mitochondria swelling, mitochondrial cristae loss and oxidative stress in cardiac tissue. The protective effect of MSC-EVs was confirmed by the delayed increase of the cardiac-specific enzymes CK and TnC in the perfusate and the reduction of caspase-3+ cells in tissue sections. ConclusionMSC-EVs improve graft quality by preserving the mitochondrial ultrastructure protecting the myocardium against oxidative stress, reducing apoptosis of cardiac cells and preventing the increase of pro-inflammatory cytokines.

Δ(9)-tetrahydrocannabinol protects cardiac tissue against endoplasmic reticulum and oxidative stresses, apoptosis, and inflammation in rats with hyperinsulinemia.

In our study, we aimed to examine how δ(9)-tetrahydrocannabinol (THC) administration to hyperinsulinemia (HI) model rats would change endoplasmic reticulum stress (ERS), apoptosis, inflammation, and oxidative stress in cardiac tissue. Rats were divided into four groups (n = 32): Control (C), THC, HI, and Treatment (Tre). Fructose (10%) in the drinking water was given to HI and Tre rats for 12 weeks. 1.5 mg/kg/d THC was given intraperitoneally to THC and Tre rats in the last 4 weeks of the experiment. The mRNA expressions of ERS and apoptosis markers in the cardiac tissue were detected. TNF-α concentration and oxidative stress were also analyzed. THC treatment in rats with HI ameliorated the overexpression of GRP-78, IRE1α, ATF6, ATF4, CHOP, Cas-12, Cas-8, Cas-9, and Cas-3 mRNAs, markers of ERS and apoptosis (P < .0001 for all). In addition, THC has been shown to reduce inflammation in the Tre group by causing a decrease in increased cardiac TNF-α levels (P < .01). Moreover, THC prevented cardiac tissue damage by regulating the degraded oxidative stress marker levels and antioxidant enzyme activities in HI. Our findings suggest that THC treatment in rats with HI exhibited a significant effect in ameliorating cardiac tissue damage by improving the antioxidant defense system, inflammation, apoptosis, ERS, and oxidative stress.

Myeloperoxidase is a critical mediator of anthracycline-induced cardiomyopathy

Cardiotoxicity is a major complication of anthracycline therapy that negatively impacts prognosis. Effective pharmacotherapies for prevention of anthracycline-induced cardiomyopathy (AICM) are currently lacking. Increased plasma levels of the neutrophil-derived enzyme myeloperoxidase (MPO) predict occurrence of AICM in humans. We hypothesized that MPO release causally contributes to AICM. Mice intravenously injected with the anthracycline doxorubicin (DOX) exhibited higher neutrophil counts and MPO levels in the circulation and cardiac tissue compared to saline (NaCl)-treated controls. Neutrophil-like HL-60 cells exhibited increased MPO release upon exposition to DOX. DOX induced extensive nitrosative stress in cardiac tissue alongside with increased carbonylation of sarcomeric proteins in wildtype but not in Mpo−/− mice. Accordingly, co-treatment of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) with DOX and MPO aggravated loss of hiPSC-CM-contractility compared to DOX treatment alone. DOX-treated animals exhibited pronounced cardiac apoptosis and inflammation, which was attenuated in MPO-deficient animals. Finally, genetic MPO deficiency and pharmacological MPO inhibition protected mice from the development of AICM. The anticancer efficacy of DOX was unaffected by MPO deficiency. Herein we identify MPO as a critical mediator of AICM. We demonstrate that DOX induces cardiac neutrophil infiltration and release of MPO, which directly impairs cardiac contractility through promoting oxidation of sarcomeric proteins, cardiac inflammation and cardiomyocyte apoptosis. MPO thus emerges as a promising pharmacological target for prevention of AICM.

Potential inhibitory effect of geraniol isolated from lemongrass (Cymbopogon commutatus Stapf) on tilmicosin-induced oxidative stress in cardiac tissue

An experimental study has been conducted to investigate the efficacy of geraniol (GNL) isolated from lemomgrass in protecting against cardiac toxicity induced by tilmicosin (TIL) in albino mice. Compared to TIL-treated mice, those supplemented with GNL had a thicker left ventricular wall and a smaller ventricular cavity. Studies of TIL animals treated with GNL showed that their cardiomyocytes had markedly changed in diameter and volume, along with a reduction in numerical density. After TIL induction, animals showed a significant increase in the protein expression of TGF-β1, TNF-α, nuclear factor kappa B (NF-kB), by 81.81, 73.75 and 66.67%, respectively, and hypertrophy marker proteins ANP, BNP, and calcineurin with respective percentages of 40, 33.34 and 42.34%. Interestingly, GNL significantly decreased the TGF-β1, TNF-α, NF-kB, ANP, BNP, and calcineurin levels by 60.94, 65.13, 52.37, 49.73, 44.18 and 36.84%, respectively. As observed from histopathology and Masson’s trichrome staining, supplementation with GNL could rescue TIL-induced cardiac hypertrophy. According to these results, GNL may protect the heart by reducing hypertrophy in mice and modulating biomarkers of fibrosis and apoptosis.

Chromium picolinate supplementation improves cardiac performance in hypoxic rats

Background Conditions associated with chronic hypoxia increase morbidity and mortality attributable to cardiovascular complications. Myocardial hypoxia is a common feature in several diseases including: stroke, infarction, anaemia, chronic lung diseases, obstructive sleep apnoea and cyanotic congenital heart defects. The present study was planned to investigate the cardiovascular effects of chronic intermittent hypoxia and its association with increased myocardial oxidative stress. In addition, to evaluate the protective effect of chromium supplementation, aiming at achieving an alternative that may enable to devise a therapy for hypoxic patients. Methods Male rats were allocated into three groups: control group (normoxic), untreated hypoxic group (exposed to hypoxia 8 h/day, 5 days/week for 6 weeks) and hypoxic group supplemented with chromium picolinate (90 µg/kg/day by gavage). Rats were subjected to measurement of body weight, haematocrit value, mean arterial blood pressure, heart rate and ECG recording. Cardiac activities of isolated hearts were studied on Langendorff preparation under basal conditions and in response to ischaemia/reperfusion. Thereafter, cardiac weights were determined and cardiac tissue catalase activity as well as malondialdhyde level were assessed. Results Significant results were obtained upon exposure to hypoxia including; low body weight, increased haematocrit, elevated blood pressure, left ventricular hypertrophy and impaired cardiac activities, basally and in response to ischaemia/reperfusion challenges, associated with increased oxidative stress in cardiac tissue. At the same time, chromium supplementation increased body weight, lowered blood pressure, reduced ventricular hypertrophy and significantly improved the cardiac performance. Conclusion Chromium supplementation confers protection against hypoxia-induced cardiovascular dysfunction by improvement of the antioxidant capacity.

Effects of four weeks lasting aerobic physical activity on cardiovascular biomarkers, oxidative stress and histomorphometric changes of heart and aorta in rats with experimentally induced hyperhomocysteinemia.

The aim of this study was to examine the effects of hyperhomocysteinemia and aerobic physical activity on changes of cardiovascular biomarkers in sera, oxidative stress in cardiac tissue, and histomorphometric parameters of heart and aorta in rats. Experiments were conducted on male Wistar albino rats organized into four groups (n = 10, per group): C (control group): 0.9% NaCl 0.2mL/day; H (homocysteine group): homocysteine 0.45µmol/g b.w./day; CPA (control + physical activity group): 0.9% NaCl 0.2mL/day and a program of physical activity on a treadmill; and HPA (homocysteine + physical activity group) homocysteine 0.45µmol/g b.w./day and a program of physical activity on a treadmill. Substances were applied subcutaneously twice a day. Lipid peroxidation and relative activity of Mn-superoxide dismutase isoform were significantly higher in active hyperhomocysteinemic rats in comparison to sedentary animals. Atherosclerotic plaques were detected in aorta samples of active hyperhomocysteinemic rats and also, they had increased left ventricle wall and interventricular septum, and transverse diameter of cardiomyocytes compared to sedentary groups. Aerobic physical activity in the condition of hyperhomocysteinemia can lead to increased oxidative stress in cardiac tissue and changes in histomorphometric parameters of the heart and aorta, as well increased lipid parameters and cardiac damage biomarkers in sera of rats.

Biochanin A Attenuates Cardiomyopathy in Type 2 Diabetic Rats by Increasing SIRT1 Expression and Reducing Oxidative Stress.

Diabetic cardiomyopathy is one of the major complications in type 2 diabetes associated with myocardial structure abnormality and major cause of morbidity in type 2 diabetic patients. Biochanin A is a methylated isoflavone present in flowering tops of Trifolium pratense reported for anti-inflammatory, anti-oxidant, anti-infective, anti-cancer and anti-diabetic activity. The study was designed to assess the efficacy of Biochanin A in type 2 diabetic cardiomyopathy. Type 2 diabetes was induced in rats feeding high fat diet for two weeks and administration of single low dose of streptozotocin. Biochanin A was administered for 16 weeks orally once in a day (10, 20 and 40 mg/kg of body weight). Various parameters such as blood glucose, cardiac markers, oxidative stress and hemodynamic parameters, immunohistochemical, histopathological investigation and SIRT1 expression were measured at the end of the study. Biochanin A treatment resulted into reduction in plasma concentration of cardiac markers along with reduction in hyperglycemia, hyperlipidemia and oxidative stress in cardiac tissue. Biochanin A treated animals also demonstrated improvement in hemodynamic parameters. Diabetic animals treated with different doses of Biochanin A shown increased SIRT1 expression in cardiac tissue, and also confirmed reduced cardiac hypertrophy and cardiac protection in histopathological study. Outcome of the study indicates that Biochanin A is the potential candidate to control hyperglycemia, oxidative stress and improve SIRT1 expression in cardiac tissue. Biochanin A might be considered as potential candidate to control progression of cardiomyopathy in type 2 diabetes mellitus.

Daidzein mitigates myocardial injury in streptozotocin-induced diabetes in rats

AimPresent study focuses on the effect of daidzein in an experimental model of diabetic cardiomyopathy in rats. Materials and methodsDiabetes was induced in male Sprague Dawley rats by a single intraperitoneal injection of STZ at dose 55 mg/kg. Daidzein treatment was started after six weeks of diabetes induction. Animals received daidzein at a dose of 25, 50, and 100 mg/kg orally for the next four weeks. Key findingsDiabetic control animals showed significant prolongation in QT interval, PR interval, and R wave amplitude as compared to normal control animals. Treatment with daidzein at dose 100 mg/kg significantly normalized the QT interval, PR interval, and R wave amplitude. A significant reduction in QRS duration was observed in diabetic animals. Treatment with daidzein significantly improved the QRS duration after treatment. Hemodynamic parameters like systolic pressure (SBP), diastolic pressure (DBP) and mean atrial pressure (MAP) were found to be significantly decreased in diabetic animals. Treatment with daidzein at dose 100 mg/kg significantly improved the SBP, DBP, and MAP. Daidzein treatment prevented the loss of cardiac marker enzyme from heart tissue and also increased the level of AMPK and SIRT1 in plasma. Protein expression of NOX-4 and RAC-1 was also found to be reduced in cardiac tissue of daidzein treated animals. Daidzein treatment improved oxidative defense mechanism and reduced cardiac tissue necrosis and fibrosis. SignificanceFrom the results, it can be concluded that daidzein mitigates the progression of diabetic cardiomyopathy by inhibiting NOX-4 induced oxidative stress in cardiac tissue.

Effect of Quercetin and Intermittent and Continuous Exercise on Catalase, Superoxide dismutase, and Malondialdehyde in the Heart of Rats with Colon Cancer

Background: Colorectal cancer is the fourth leading cause of death globally, and the second most common cancer in Europe. About 8% of all cancer-related deaths occur due to colorectal cancer, and the highest prevalence has been reported in Asia and Eastern Europe. Methods: In this experimental study, 80 rats were divided into two groups of cases (n=70) and controls (n=10). Colorectal cancer was induced weekly in rats by subcutaneous injection of 15 mg/kg Azoxymethane. The rats were then divided into 7 experimental subgroups of patients, saline, quercetin, intermittent exercise, continuous exercise, quercetin plus intermittent, and quercetin plus continuous exercise. Oxidative stress biomarkers, including superoxide dismutase (SOD), catalase (CAT), and malondialdehyde (MDA) were measured in the rats’ heart tissue by the ELISA method. Data were analyzed using ANOVA by SPSS software. Results: Oxidative stress in heart cells increased due to colorectal cancer. Quercetin alone or in combination with exercise significantly increased mean levels of CAT and SOD in the heart tissue of rats compared with patient and saline groups (P&lt;0.0001). In contrast, the MDA level was significantly decreased (P&lt;0.05). Conclusion: Colorectal cancer increased the oxidative stress in cardiac cells. Quercetin alone improved oxidative stress in cardiac tissue, and its combination with exercise was more effective.

Preconditioning with Short-term Dietary Restriction Attenuates Cardiac Oxidative Stress and Hypertrophy Induced by Chronic Pressure Overload.

Left ventricular (LV) hypertrophy and associated heart failure are becoming a more prevalent and critical public health issue with the aging of society, and are exacerbated by reactive oxygen species (ROS). Dietary restriction (DR) markedly inhibits senescent changes; however, prolonged DR is difficult. We herein investigated whether preconditioning with short-term DR attenuates chronic pressure overload-induced cardiac hypertrophy and associated oxidative stress. Male c57BL6 mice were randomly divided into an ad libitum (AL) diet or 40% restricted diet (DR preconditioning, DRPC) group for 2 weeks prior to ascending aortic constriction (AAC), and all mice were fed ad libitum after AAC surgery. Two weeks after surgery, pressure overload by AAC increased LV wall thickness in association with LV diastolic dysfunction and promoted myocyte hypertrophy and cardiac fibrosis in the AL+AAC group. Oxidative stress in cardiac tissue and mitochondria also increased in the AL+AAC group in association with increments in cardiac NADPH oxidase-derived and mitochondrial ROS production. LV hypertrophy and associated cardiac dysfunction and oxidative stress were significantly attenuated in the DRPC+AAC group. Moreover, less severe mitochondrial oxidative damage in the DRPC+AAC group was associated with the suppression of mitochondrial permeability transition and cardiac apoptosis. These results indicate that chronic pressure overload-induced cardiac hypertrophy in association with cardiac and mitochondrial oxidative damage were attenuated by preconditioning with short-term DR.

Effect of modulation of hydrogen sulfur and glutathione synthesis on oxidative and nitrosative metabolism under myocardial ischemia-reperfusion

Redox balance maintaining is a prerequisite for normal cardiomyocytes metabolism. Reperfusion injury of the heart is characterized by an explosive increase in ROS generation, cell membranes damage, dysfunction of proteins, the development of muscle contracture etc. It was shown that the hydrogen sulfide (H2S) and the precursor of its synthesis the amino acid L-cysteine provided cardioprotective effect against ischemiareperfusion, In addition, L-cysteine is one of amino acids that form an antioxidant glutathione (GSH). The aim of our work was to investigate the effect of GSH and H2S synthesis modulation on the oxidative and nitrosative stress in cardiac tissues under conditions of ischemia-reperfusion. The H2S synthesis inhibitor propargylglycine (PAG), the GSH synthesis inhibitor butionine sulfoxime (BSO) and L-cysteine were administered intraperitoneally. Next, ischemia-reperfusion of the Langendorff isolated rat heart was performed. In the tissues of rat's hearts, before and after ischemia, we determined the rate of ROS generation, content of POL products, the activity of NO synthesizing enzymes. Results of our study showed that pretreatment with PAG + L-cysteine combination prevented heart function disturbances, ROS formation, increased low molecular weight nitrosothiols content, preserved the activity of constitutive NOS and inhibited the activity of inducible NOS in the pre-ischemic period as well as in the period of reperfusion. Pretreatment with BSO in PAG + L-cysteine group significantly reduced the effectiveness of the combination and abolished cardioprotective effect. Generation of superoxide and hydroxyl anions was increased, activity of inducible NO-synthase was 3.5-fold increased comparing with PAG + L-cysteine pretreated group. Pretreatment with PAG + L-cysteine combination inhibited the formation of ROS and preserved the activity of constitutive NOS, thus providing stable production of NO. Pretreatment with BSO completely abolished an antioxidant effect of PAG + L-cysteine decreasing bioavailability of glutathione.

Pandemic Influenza Infection Persists in Cardiac Tissue and Leads to MLKL-Dependent Proteome and Phosphoproteome Remodeling During Convalescence

Influenza-related cardiac complications have been increasingly defined in the clinical setting. Recent reports support a direct link between laboratory-confirmed influenza infection and adverse cardiac events. Here, we define candidate molecular mediators underlying influenza virus-induced cardiac pathogenesis after the resolution of pulmonary infection, as well as the potential role of necroptosis in this process using mice deficient in its effector molecule MLKL. Global proteome and phosphoproteome analyses using high resolution accurate mass-based LC-MS/MS and label-free quantitation was used. Both the global proteome and the phosphoproteome profiles were significantly altered in IAV-infected mouse hearts, with significantly altered expression of mitochondrial and muscle contraction protein levels and phosphorylation states. Intriguingly, necroptosis deficient mice showed partial protection from IAV-mediated proteomic changes. We confirmed changes in energy state and mitochondrial dysfunction in vitro and define molecular candidates for therapeutics targeting necroptosis and oxidative stress in cardiac tissue after influenza infection.

Nrf2 deficiency aggravates PM2.5-induced cardiomyopathy by enhancing oxidative stress, fibrosis and inflammation via RIPK3-regulated mitochondrial disorder.

PM2.5 is a well-known air pollutant threatening public health, and long-term exposure to PM2.5 increases the risk of cardiovascular diseases. Nrf2 plays a pivotal role in the amelioration of PM2.5-induced lung injury. However, if Nrf2 is involved in PM2.5-induced heart injury, and the underlying molecular mechanisms have not been explored. In this study, wild type (Nrf2+/+) and Nrf2 knockout (Nrf2-/-) mice were exposed to PM2.5 for 6 months. After PM2.5 exposure, Nrf2-/- mice developed severe physiological changes, lung injury and cardiac dysfunction. In the PM2.5-exposed hearts, Nrf2 deficiency caused significant collagen accumulation through promoting the expression of fibrosis-associated signals. Additionally, Nrf2-/- mice exhibited greater oxidative stress in cardiac tissues after PM2.5 exposure. Furthermore, PM2.5-induced inflammation in heart samples were accelerated in Nrf2-/- mice through promoting inhibitor of α/nuclear factor κB (IκBα/NF-κB) signaling pathways. We also found that Nrf2-/- aggravated autophagy initiation and glucose metabolism disorder in hearts of mice with PM2.5 challenge. Cardiac receptor-interacting protein kinase 3 (RIPK3) expression triggered by PM2.5 was further enhanced in mice with the loss of Nrf2. Collectively, these results suggested that strategies for enhancing Nrf2 could be used to treat PM2.5-induced cardiovascular diseases.

Remifentanil Induces Cardio Protection Against Ischemia/Reperfusion Injury by Inhibiting Endoplasmic Reticulum Stress Through the Maintenance of Zinc Homeostasis.

Although it is well known that remifentanil (Rem) elicits cardiac protection against ischemia/reperfusion (I/R) injury, the underlying mechanism remains unclear. This study tested if Rem can protect the heart from I/R injury by inhibiting endoplasmic reticulum (ER) stress through the maintenance of zinc (Zn) homeostasis. Isolated rat hearts were subjected to 30 minutes of regional ischemia followed by 2 hours of reperfusion. Rem was given by 3 consecutive 5-minute infusions, and each infusion was followed by a 5-minute drug-free perfusion before ischemia. Total Zn concentrations in cardiac tissue, cardiac function, infarct size, and apoptosis were assessed. H9c2 cells were subjected to 6 hours of hypoxia and 2 hours of reoxygenation (hypoxia/reoxygenation [H/R]), and Rem was given for 30 minutes before hypoxia. Metal-responsive transcription factor 1 (MTF1) overexpression plasmids were transfected into H9c2 cells 48 hours before hypoxia. Intracellular Zn level, cell viability, and mitochondrial injury parameters were evaluated. A Zn chelator N,N,N',N'-tetrakis-(2-pyridylmethyl) ethylenediamine (TPEN) or an ER stress activator thapsigargin was administrated during in vitro and ex vivo studies. The regulatory molecules related to Zn homeostasis and ER stress in cardiac tissue, and cardiomyocytes were analyzed by Western blotting. Rem caused significant reversion of Zn loss from the heart (Rem + I/R versus I/R, 9.43 ± 0.55 vs 7.53 ± 1.18; P < .05) by suppressing the expression of MTF1 and Zn transporter 1 (ZnT1). The inhibited expression of ER stress markers after Rem preconditioning was abolished by TPEN. Rem preconditioning improved the cardiac function accompanied by the reduction of infarct size (Rem + I/R versus I/R, 21% ± 4% vs 40% ± 6%; P < .05). The protective effects of Rem could be reserved by TPEN and thapsigargin. Similar effects were observed in H9c2 cells exposed to H/R. In addition, MTF1 overexpression blocked the inhibitory effects of Rem on ZnT1 expression and ER stress at reoxygenation. Rem attenuated the collapse of mitochondrial membrane potential (ΔΨm) and the generation of mitochondrial reactive oxygen species by inhibiting ER stress via cardiac Zn restoration (Rem + H/R versus H/R, 79.57% ± 10.62% vs 58.27% ± 4.32%; P < .05). Rem maintains Zn homeostasis at reperfusion by inhibiting MTF1 and ZnT1 expression, leading to the attenuation of ER stress and cardiac injury. Our findings provide a promising therapeutic approach for managing acute myocardial I/R injury.

Oxidative Stress in Cardiac Tissue of Patients Undergoing Coronary Artery Bypass Graft Surgery: The Effects of Overweight and Obesity.

Background Obesity is one of the major cardiovascular risk factors and is associated with oxidative stress and myocardial dysfunction. We hypothesized that obesity affects cardiac function and morbidity by causing alterations in enzymatic redox patterns. Methods Sixty-one patients undergoing coronary artery bypass grafting (CABG) were included in the study. Excessive right atrial myocardial tissue emerging from the operative connection to the extracorporeal circulation was harvested. Patients were assigned to control (n = 19, body mass index (BMI): <25 kg/m2), overweight (n = 25, 25 kg/m2 < BMI < 30 kg/m2), or obese (n = 17, BMI: >30 kg/m2) groups. Oxidative enzyme systems were studied directly in the cardiac muscles of patients undergoing CABG who were grouped according to BMI. Molecular biological methods and high-performance liquid chromatography were used to detect the expression and activity of oxidative enzymes and the formation of reactive oxygen species (ROS). Results We found increased levels of ROS and increased expression of ROS-producing enzymes (i.e., p47phox, xanthine oxidase) and decreased antioxidant defense mechanisms (mitochondrial aldehyde dehydrogenase, heme oxygenase-1, and eNOS) in line with elevated inflammatory markers (vascular cell adhesion molecule-1) in the right atrial myocardial tissue and by trend also in serum (sVCAM-1 and CCL5/RANTES). Conclusion Increasing BMI in patients undergoing CABG is related to altered myocardial redox patterns, which indicates increased oxidative stress with inadequate antioxidant compensation. These changes suggest that the myocardium of obese patients suffering from coronary artery disease is more susceptible to cardiomyopathy and possible damage by ischemia and reperfusion, for example, during cardiac surgery.

Alleviation of Cardiac Damage by Dietary Fenugreek (Trigonella foenum-graecum) Seeds is Potentiated by Onion (Allium cepa) in Experimental Diabetic Rats via Blocking Renin-Angiotensin System.

Hyperglycemia is one of the metabolic and homeostatic abnormalities that increase the cardiovascular mortality in diabetic patients by increased oxidative stress. We have recently reported amelioration of oxidative stress in cardiac tissue by dietary fenugreek (Trigonella foenum-graecum) seeds and onion (Allium cepa) in streptozotocin-induced diabetic rats. The mechanistic aspects of the cardio-protective influence of dietary fenugreek seeds (10%) and onion (3% powder) both individually and in combination on hyperglycemia-mediated cardiac damage was further investigated in this study on streptozotocin-induced diabetic rats. Cardio-protective influence of these dietary spices was evidenced by their blocking potential on renin-angiotensin system. This might be the consequence of reduced activation of angiotensin-converting enzyme (ACE) and angiotensin type 1 receptor (AT1) in cardiac tissue. The combination produced an additive effect on ACE and AT1 protein and mRNA expressions. Increased expression of type IV collagen, fibronectin, Bax, 4-hydroxynonenal, iNOS and metabolites of nitric oxide (nitrate/nitrite) along with disturbed PUFA-to-SFA ratio and activities of cardiac marker enzymes in blood confirmed the myocardial damage. Dietary fenugreek seed, onion and fenugreek+onion were found to ameliorate these pathological changes in the cardiovascular system. The beneficial effect being higher with the combination sometime amounting to additive (iNOS expression) or even a synergistic (cardiac Bax and type IV collagen expression and circulatory marker enzymes) in diabetic rats. Thus, the results of present investigation suggested that the combination of fenugreek seeds and onion offers higher beneficial influence in ameliorating cardiac damage accompanying diabetes.

Melatonin ameliorates myocardial apoptosis by suppressing endoplasmic reticulum stress in rats with long‑term diabetic cardiomyopathy.

The effects of melatonin (MLT), which exerts cardioprotective effects against myocardial apoptosis, in long‑term diabetic cardiomyopathy are not currently well defined. The present study aimed to investigate how MLT protects the heart through modulating myocardial apoptosis in rats with type 2 diabetes mellitus (DM). In total, 36 rats were randomly divided into three groups, including control (n=12), DM (n=12) and DM+MLT (n=12) groups. The results demonstrated that, in DM rats, a significant increase was observed in the serum fasting blood glucose and lipid levels, in addition to insulin resistance and cardiac dysfunction, which were attenuated in DM rats treated with MLT. Additionally, cellular apoptosis in rats with DM was increased, and the expression of Bcl‑2 was downregulated, while levels of Bcl‑2‑associated X and caspase‑3 were upregulated, and these observations were reversed by MLT, as determined by TUNEL and western blot analysis, respectively. As increased endoplasmic reticulum (ER) stress induced by hyperglycemia is reported to be a factor for apoptosis, the present study also determined the expression of proteins associated with ER stress in cardiac tissues following MLT treatment by western blotting. The results further indicated that MLT decreased the expression of ER stress hallmarks, including CCAAT/enhancer‑binding protein homologous protein, glucose‑regulated protein 78, protein kinase RNA‑like endoplasmic reticulum kinase (PERK) and activating transcription factor 6α in cardiac tissues. In conclusion, the results of the present study indicate that MLT may protect heart by ameliorating cardiac ER stress‑induced apoptosis in diabetic cardiomyopathy.

Cardiac oxidative stress following maternal separation stress was mitigated following adolescent voluntary exercise in adult male rat

Early life stress (ELS) is known as a risk factor for the development of depression and its associated comorbidities, such as cardiomyopathy in depressed patients. Mitochondrial dysfunction plays a critical role in the pathophysiology of depression and cardiovascular diseases. Evidence indicates that regular physical activity has therapeutic effects on both mood and cardiovascular disorders. Therefore, the voluntary running wheel exercise (RW) during adolescence may be able to attenuate the negative impact of maternal separation stress (MS) as a valid animal model of depression on the behavior and cardiac mitochondrial function of adult rats. To do this, we applied MS to rat pups by separating them from their mothers for 180min during the postnatal day (PND) 2 to PND 14. Next, the animals were randomly divided into different treatment groups (fluoxetine [FLX] and RW) and received the treatments during adolescence, between PND 28 to PND 60. Then, we evaluated the effects of MS on the rat behaviors test, and finally, we assessed reactive oxygen species, mitochondrial glutathione, ATP and cytochrome c release in the cardiac tissue of animals. Our results showed that depressive-like behaviors following MS in adult male rats were associated with oxidative stress in cardiac tissue. Further, we found that treating animals with chronic FLX or RW during adolescence improved animal's behavior as well as cardiac mitochondrial function. The results of this study highlight the importance of adolescence as a period during which treating animals with non-pharmacological agents has significant protective effects against the negative influence of ELS on mood and cardiac energy hemostasis.

Hydrogen Sulfide Improves Cardiomyocyte Function in a Cardiac Arrest Model.

BackgroundCardioplegic arrest is a common procedure for many types of cardiac surgery, and different formulations have been proposed to enhance its cardio-protective effect. Hydrogen sulfide is an important signaling molecule that has cardio-protective properties. We therefore studied the cardio-protective effect of hydrogen sulfide in cardiac cell culture and its potential therapeutic use in combination with cardioplegia formulations.Materials/MethodsWe added hydrogen sulfide donor GYY4137 to HL-1 cells to study its protective effect in nutrient starved conditions. In addition, we tested the potential use of GYY4137 when it is added into two different cardioplegia formulations: Cardi-Braun® solution and del Nido solution in an ex vivo Langendorff perfused rat hearts model.ResultsWe observed that eight-hour pre-treatment with GYY4137 significantly suppressed apoptosis in nutrient-starved HL-1 cells (28% less compared to untreated cells; p<0.05), maintained ATP content, and reduced protein synthesis. In ex vivo experiments, Cardi-Braun® and del Nido cardioplegia solutions supplemented with GYY4137 significantly reduced the pro-apoptotic protein caspase-3 content and preserved ATP content. Furthermore, GYY4137 supplemented cardioplegia solutions decreased the S-(5-adenosyl)-L-methionine/S-(adenosyl)-L-homocysteine ratio, reducing the oxidative stress in cardiac tissue. Finally, heart beating analysis revealed the preservation of the inter-beat interval and the heart rate in del Nido cardioplegia solution supplemented with GYY4137.ConclusionsGYY4137 preconditioning preserved energetic state during starved conditions, attenuating the cardiomyocytes apoptosis in vitro. The addition of GYY4137 to cardioplegia solutions prevented apoptosis, ATP consumption, and oxidative stress in perfused rat hearts, restoring its electrophysiological status after cardiac arrest. These findings suggested that GYY4137 sulfide donor may improve the cardioplegia solution performance during cardiac surgery.