Alterations In Cardiac Tissue Research Articles

T-2 toxin induces cardiac fibrosis by causing metabolic disorders and up-regulating Sirt3/FoxO3α/MnSOD signaling pathway-mediated oxidative stress

T-2 toxin, an omnipresent environmental contaminant, poses a serious risk to the health of humans and animals due to its pronounced cardiotoxicity. This study aimed to elucidate the molecular mechanism of cardiac tissue damage by T-2 toxin. Twenty-four male Sprague-Dawley rats were orally administered T-2 toxin through gavage for 12 weeks at the dose of 0, 10, and 100 nanograms per gram body weight per day (ng/(g·day)), respectively. Morphological, pathological, and ultrastructural alterations in cardiac tissue were meticulously examined. Non-targeted metabolomics analysis was employed to analyze alterations in cardiac metabolites. The expression of the Sirt3/FoxO3α/MnSOD signaling pathway and the level of oxidative stress markers were detected. The results showed that exposure to T-2 toxin elicited myocardial tissue disorders, interstitial hemorrhage, capillary dilation, and fibrotic damage. Mitochondria were markedly impaired, including swelling, fusion, matrix degradation, and membrane damage. Metabonomics analysis unveiled that T-2 toxin could cause alterations in cardiac metabolic profiles as well as in the Sirt3/FoxO3α/MnSOD signaling pathway. T-2 toxin could inhibit the expressions of the signaling pathway and elevate the level of oxidative stress. In conclusion, the T-2 toxin probably induces cardiac fibrotic impairment by affecting amino acid and choline metabolism as well as up-regulating oxidative stress mediated by the Sirt3/FoxO3α/MnSOD signaling pathway. This study is expected to provide targets for preventing and treating T-2 toxin-induced cardiac fibrotic injury.

Exercise reduces hyperlipidemia-induced cardiac damage in apolipoprotein E-deficient mice via its effects against inflammation and oxidative stress

Cardiovascular disease is a high incidence and mortality rate disease worldwide. Exercise training has become an established evidence-based treatment strategy that is beneficial for many cardiovascular diseases. This study aimed to investigate the effects of exercise on hyperlipidemia-induced cardiac damage in apolipoprotein E-deficient (ApoE−/−) mice. Male ApoE−/− mice were randomly divided into the following four groups: normal diet (ND), normal diet + exercise training (ND + E), high-fat diet (HFD), and high-fat diet + exercise training (HFD + E). Exercise training consisted of swimming for 40 min, 5 days/week for 12 weeks. After 12 weeks, histopathological alterations in cardiac tissue and the serum were measured. Furthermore, the NOX4, NRF2, SIRT1, TGF-β, HO-1, collagen III, Smad3, Bax, Bak, Bcl-2, Bcl-xl, IL-1β, IL-6, and IL-18 expression levels were evaluated using immunohistochemistry and western blotting; Results: the serum levels of SIRT1, GSH-Px, and SOD were lower in ApoE−/− HFD mice compared with those in ApoE−/− HFD + E mice. Significant pathological changes were observed in the ApoE−/− HFD + E group compared with those in the ApoE−/− HFD group. Increased levels of oxidative stress, fibrosis, and apoptosis, and decreased antioxidant expression in the ApoE−/− HFD group compared with those in ApoE−/− HFD + E mice. Exercise exerts protective effects against cardiac damage caused by hyperlipidemia.

Linagliptin ameliorated cardiac fibrosis and restored cardiomyocyte structure in diabetic mice associated with the suppression of necroptosis.

Linagliptin is a selective dipeptidyl peptidase (DPP)-4 inhibitor capable of successfully regulating blood glucose levels. The cardiovascular protective effects of several DPP-4 inhibitors have been shown in preclinical studies; however, the detailed influence of DPP-4 inhibitors on diabetic pathological alterations in cardiac tissue has not yet been elucidated. We combined laboratory-based experiments and bioinformatics techniques to identify suitable candidate targets with significant biological pathways. Mice with streptozotocin-induced insulin deficiency diabetic model were utilized for in vivo experiments. Mice were euthanized at 24 weeks after the induction of diabetes; linagliptin intervention was carried out for 4 weeks before euthanasia. Microarray analysis of heart samples was carried out. Mice with streptozotocin-induced diabetes, but not control mice, showed cardiac fibrosis with an endothelial-mesenchymal transition program, and myocardial fiber and sarcomere disruption; linagliptin alleviated these diabetes-associated pathological alterations without altering blood glucose levels. Bioinformatics analysis utilizing a microarray dataset identified 10 hub genes that were confirmed to have human disease relevance by Gene Expression Omnibus analysis. Among these hub genes, we focused on the Sox9-necroptosis axis as a therapeutic target in diabetic hearts. Indeed, diabetic mice showed the induction of necroptosis-associated genes and the phosphorylation of RIP3 and mixed lineage kinase domain-like protein. Linagliptin showed excellent heart protection in mice with streptozotocin-induced diabetes associated with alterations in human disease-relevant hub genes. Further investigation is required to determine why DPP-4 inhibitors do not show similar superior organ-protective effects in the clinical setting.

The relationship between cardiac damage biomarkers and heart rate variability following 60min of running.

Endurance exercise may cause transient alterations in cardiac tissue. The number of studies evaluating the relationship between changes in heart rate variability (HRV) and cardiac biomarkers following an endurance event is limited. We hypothesized that there would be a time-dependent correlation between biomarkers of cardiac damage and the reduction in parasympathetic indices of HRV within 24h after 60min of running in middle-aged recreational runners. The trained, middle-aged runners who participated in this study ran 60min at a half-marathon pace on a treadmill. Blood samples (before and 0, 4, and 24h after the running test) and HRV data (before and 0, 1, 4, and 24h after the running test) were obtained. After running, cardiac biomarkers (total creatine kinase, cardiac isoform of creatine kinase, creatine kinase-index [CK-Index], cardiac troponin [cTnI]) increased significantly, and HRV measures related to parasympathetic nervous system activity decreased significantly; these measures returned to baseline levels within 24h. Finally, there were significant correlations (all p < 0.05) between the change (4h post-running vs. pre-running) in the CK-Index and the changes (post- vs pre-running) in time-domain and nonlinear measures of HRV (r -0.61 to -0.67). In addition, significant correlations (all p < 0.05) were found between the area under the cTnI curve and change (1-h post- and pre-running) in time-domain and nonlinear measures of HRV (r -0.48 to -0.51). The correlation between HRV and cardiac biomarkers indicates that HRV analysis may be an alternative approach to determine the magnitude of cardiac stress after endurance exercises.

Alterations in Cardiac Tissue of a Natural Obese Rat Model: Implications for Obesity-Associated Cardiomyopathy

Alterations in Cardiac Tissue of a Natural Obese Rat Model: Implications for Obesity-Associated Cardiomyopathy

Macrophage phenotype and function are dependent upon the composition and biomechanics of the local cardiac tissue microenvironment.

Macrophage accumulation and nitrosative stress are known mechanisms underlying age-related cardiovascular pathology and functional decline. The cardiac muscle microenvironment is known to change with age, yet the direct effects of these changes have yet to be studied in-depth. The present study sought to better elucidate the role that biochemical and biomechanical alterations in cardiac tissue have in the altered phenotype and functionality of cardiac resident macrophages observed with increasing age. To accomplish this, naïve bone marrow derived macrophages from young mice were seeded onto either functionalized poly-dimethyl-siloxane hydrogels ranging in stiffness from 2kPA to 64kPA or onto tissue culture plastic, both of which were coated with either young or aged solubilized mouse cardiac extracellular matrix (cECM). Both biomechanical and biochemical alterations were found to have a significant effect on macrophage polarization and function. Increased substrate stiffness was found to promote macrophage morphologies associated with pro-inflammatory macrophage activation, increased expression of pro-inflammatory inducible nitric oxide synthase protein with increased nitric oxide secretion, and attenuated arginase activity and protein expression. Additionally, exposure to aged cECM promoted attenuated responsivity to both canonical pro-inflammatory and anti-inflammatory cytokine signaling cues when compared to young cECM treated cells. These results suggest that both biomechanical and biochemical changes in the cardiovascular system play a role in promoting the age-related shift towards pro-inflammatory macrophage populations associated with cardiovascular disease development.

Impact of Monosodium Glutamate Intake on Heart Structure of Neonate Albino Rats and The Protective Role of Vitamin C

Background: Despite worldwide use of monosodium glutamate (MSG) as a flavor enhancer, its consumption has been an alarm due to daily exposure without definitive safety or exact limit. Vitamin C has an antioxidant activity. Objective: to clarify effects of neonatal MSG intake on heart structure of male albino rat pups and the possible modifying role of vitamin C and to assess reversibility of these effects.Material and Methods: 40 male albino rats at postnatal day 1(PD1) were allocated to three groups; control, group B administered MSG (4 mg/gm bw/day) and group C administered previous dose of MSG plus vitamin C (500 mg/kg bw/day) for 10 days. Groups B and C were subdivided according to animal sacrification age into B1, C1 sacrificed at PD10 (after the last dose of treatment) and B2, C2 sacrificed at PD30 (20 days after treatment cessation). At experimental end, left ventricular specimens were processed for histopathological, immunohistochemical and morphometric studies. The Results: Histologically, group B1 revealed massive degenerative changes including marked muscle fibers disruption, degeneration, separation with increased CT cells and fibroblasts, dilated congested capillaries and extravasated hemorrhage. Cardiomyocytes showed nuclear pyknosis, cytoplasmic coagulative necrosis and vacuolation. Previous changes were still present in group B2 but with less degree. MSG plus vitamin C resulted in greatly restored normal cardiomyocyte architecture in group C1 but complete recovery was observed in group C2. The mean area percentage of collagen fibers, vimentin and iNOS expressions showed high significant increase in B1, B2, low significant elevation in C1 but non-significantly different in C2 relative to control group. Conclusion: MSG induced myocardial toxicity in early postnatal period. Vitamin C greatly ameliorated histopathological and immunohistochemical alterations in cardiac tissue. MSG withdrawal for 20 days showed mild improvement but withdrawal after vitamin C administration was more effective in reversibility of MSG toxicity.

P.004 Pharmacological activation of trace amine-associated receptor 1 decreases nicotine self-administration in rodents without development of tolerance

Apelin, an adipocyte-derived factor, exhibited a number of cardioprotective properties; however, its effect in diabetes which is a major risk factor for cardiovascular disease (CVD) needs to be further studied. So this work was designed to evaluate the effect of apelin on diabetes and its associated cardiac hypertrophy with its possible underlying protective mechanisms.Thirty male adult Wistar rats were categorized into three groups, 10 rats each, normal control group: received standard food and water regime. Diabetic control group: received streptozotocin (STZ) at a dose of (55 mg/kg, i.p., once) dissolved in citrate buffer (pH 4.5). Apelin-13 treated diabetic group: STZ diabetic rats received an intra peritoneal injection of apelin-13 at a dose of (100 nmol/kg/day), and given daily for 8 weeks. at the end of the experiment, oral glucose tolerance test (OGTT) was assayed, then rats were sacrificed and serum glucose, insulin, triglyceride (TG), total cholesterol, high density lipoprotein (HDL) cholesterol, serum lactate dehydrogenase (LDH) and serum creatine kinase – MB (CK-MB) were measured, together with cardiac hypertrophy index (CHI), left ventricular hypertrophy index (LVHI) and left ventricular protein and collagen content levels. Myocardial superoxide dismutase (SOD), catalase, reduced glutathione (GSH) and malondialdehyde (MDA) were determined in the myocardial tissue of experimental rats.Treatment with apelin-13 improved hyperglycemia and hyperlipidemia, and significantly protected against STZ-induced structural alterations in cardiac tissue, it also produced a significant reduction in MDA while it elevated the level of antioxidant enzymes in hearts of diabetic rats.This study suggested that apelin can ameliorate diabetes and its associated myocardial hypertrophy through mainly its anti diabetic, anti hyperlipidemic and anti oxidative stress properities.

Repeated dose of meloxicam induces genotoxicity and histopathological changes in cardiac tissue of mice

Meloxicam is the non-steroidal anti-inflammatory drug most used in small animals; however, studies on genotoxicity, oxidative stress, and histopathologic alterations in cardiac tissue are limited, especially at therapeutical doses used in these animals. This study evaluated the toxic effects caused by the treatment involving repeated low at higher doses of meloxicam in mice, by genotoxicity, oxidative stress, and histopathological parameters. Mice (CF1, male) received, by gavage, meloxicam at the therapeutic dose indicated for small animals (0.1 mg/kg) and at higher doses (0.5 and 1 mg/kg) for 28 days. Later, they were euthanized for blood and organ analysis. Oxidative stress was analyzed by the plasma ferric reduction capacity (FRAP) and catalase, and genotoxicity, by the comet assay and the micronucleus test. Heart, liver, lung, and kidney tissues were analyzed by the histology, and stomach and duodenum were analyzed with a magnifying glass. The relative weight of organs did not present significant alterations. However, congestion of duodenum vessels was observed at the three tested doses and caused hyperemia of stomach mucosa at 1 mg/kg. In the heart histology there was a reduction in the number of cardiomyocytes, accompanied by an increase in cell diameter (possible cell hypertrophy) dose-dependent. The highest tested dose of meloxicam also increased the DNA damage index, without alterations in the micronucleus test. Meloxicam did not affect the catalase activity but increased the FRAP (1 mg/kg). Meloxicam at the dose prescribed for small animals could potentially cause cardiac histopathologic alterations and genotoxic effects.

Protective potency of Astragalus polysaccharides against tilmicosin- induced cardiac injury via targeting oxidative stress and cell apoptosis-encoding pathways in rat.

Tilmicosin (Til) was purposed to be used in the treatment of a wide range of respiratory diseases in livestock. However, undesirable adverse effects, cardiac toxicity, in particular, may be associated with Til therapy. In the present study, the response of adult rats administered Til subcutaneously at different doses (10, 25, 50, 75, and 100mg/kg b.w.; single injection) was evaluated. Astragalus polysaccharide (AP) at two doses (100 and 200mg/kg b.w.; intraperitoneally) was investigated for its potential to counteract the cardiac influences, involving the oxidative stress-induced damage and apoptotic cell death, elicited by the Til treatment at a dose of 75mg/kg b.w. in rats. Til induced mortalities and altered the levels of the biomarkers for the cardiac damage, particularly in the rats treated with the doses of 75 and 100mg/kg b.w.; similarly, morphological alterations in cardiac tissue were seen at all studied doses. AP was found to cause a significant (P˂0.05) decline in the levels of impaired cardiac injury markers (troponin, creatine phosphokinase, and creatine phosphokinase-MB), improvement in the antioxidant endpoints (total antioxidant capacity), and attenuation in the oxidative stress indices (total reactive oxygen species, 8-hydroxy-2-deoxyguanosine, lipid peroxides [malondialdehyde], and protein carbonyl), associated with a significant (P˂0.05) modulation in the mRNA expression levels of the encoding genes (Bcl-2, Bax, caspase-3, P53, Apaf-1, and AIF), related to the intrinsic pathway of apoptotic cell death in the cardiac tissue. AP administration partially restored the morphological changes in the rat's heart. The highest protective efficacy of AP was recorded at a dose level of 200mg/kg b.w. Taken together, these results indicated that AP is a promising cardioprotective compound capable of attenuating Til-induced cardiac impact by protecting the rat cardiac tissue from Til-induced apoptosis when administered concurrently with and after the Til injection.

Therapeutic Role of Coenzyme Q10 or/and α-lipoic acid on Cardiac Functions in Obese/Hypertensive Rats

This study focuses on the relationship between obesity and hypertension and the possible amelioration effects of co-enzyme Q10 (CoQ10) or/and α-lipoic acid (ALA) and their mixture on histological and physiological changes in rat heart. To achieve this purpose, a comparison took place between normal control rats group (20 rats) and obese/hypertensive rats group (24 rats). The obese/hypertensive rats were injected (i.v) with Poloxamer-407(P-407) as a single dose (1g/kg b.wt dissolved in 1ml cold saline) to induce obesity and with the aid of oro-gastric tube 1g sodium chloride salt/kg b.wt/day for 30 days for induction of hypertension. Control rats group (20 rats) were divided into 5 animals (normal control rats subgroup), 5 animals treated with 200mg CoQ10/kg b.wt /day (Normal + CoQ10 rats), 5 rats treated with 100mg ALA/kg b.wt /day (Normal + ALA rats) and the last 5 animals treated with both antioxidants as the above subgroups (Normal + CoQ10 + ALA) by oro-gastric tube. The 24 obese/hypertensive rats were divided to four subgroups, the first subgroup (6 obese/hypertensive rats), the second subgroup (6 rats) was treated with 200mg CoQ10/kg/b.wt/day (obese/hypertensive rats + CoQ10 rats), the third (6 rats) was treated with 100mg ALA/kg b.wt/day (obese/hypertensive rats + ALA rats) and the last 6 animals were treated with both antioxidants as above described (obese/hypertensive rats + CoQ10 + ALA). All rats were dissected after 4 week experimental duration. Histological alterations in cardiac tissue of obese/hypertensive rats included lack of striation of myocytes with pyknotic nuclei; interstitial edema; congested blood vessels and mononuclear cellular infiltration in expanded intracellular spaces. After the induction of obesity and hypertension in rats and in comparison to normal control animals, the results showed significant (P˂0.05) increase in serum concentrations of cholesterol, triglycerides, HDL-cholesterol and LDL-cholesterol. Also, remarkable increments in the serum heart enzymes activities of creatine kinase (CK), creatine kinase -MB (CK-MB), lactate dehydrogenase (LDH) and aspartate aminotransferase (AST). The increment of serum levels of heart fatty acid binding protein (H-FABP) and endotheline-1 (ET-1) occurred. On the other hand, a significant (P˂0.05) decrease in the level of serum total nitric oxide was recorded in obese/hypertensive rats compared with those corresponding normal control ones. When obese/hypertensive rats subgroups were treated with CoQ10 or/and ALA, considerable ameliorative effects in all previous studied parameters were pronounced dependent on certain mechanisms discussed according to available recent researches. Moreover, histological studies of the heart also revealed a definite ameliorative effect of these antioxidants as regards tissue damage and structural integrity.

The protective role of sesame oil against bisphenol A-induced cardiotoxicity: a histological and immunohistochemical study

Introduction Bisphenol-A (BPA), an estrogenic compound, is used in the manufacture of polycarbonate plastics and epoxy resins. Sesame oil (SO) is a potent antioxidant dietary source for human health. Aim The present study was conducted to estimate the protective effects of SO against BPA-induced cardiotoxicity. Materials and methods Thirty two adult rats were divided into 4 equal groups eight rat for each; Control group, 2 Treated group, one group received BPA (25 mg/kg b wt) orally 5 times/weak for 4 weeks and other group rats received (50 mg/kg b. wt) orally 5 times /weak for 4 weeks. Protected group received sesame oil orally at a dose 10 mL/kg b wt orally daily for 4 weeks to the rat group which received the high dose of BPA. After the end of treatments, the heart of each killed animal was subjected to histopathological examination by hematoxylin and eosin, Masson’s, and NOS stain. In addition, blood was collected for biochemical assessment of the enzymes. Results Administration of high-dose BPA (50 mg/kg b. wt) significantly increased the weight of rats. Several histopathological alterations in cardiac tissue and elevation in malondialdehyde, creatine phosphokinase-MB, and glutathione-S-transferase activity and reduction of glutathione and catalase occurred when compared with the control. Low-dose BPA (25 mg/kg b. wt) produced mild histopathological effect on the heart. On the contrary, oral gavages of SO with BPA was effective in the reduction of weight, amelioration of histopathological alterations, and in the reduction of the malondialdehyde, creatine phosphokinase-MB, and glutathione-S-transferase activity levels and elevation of glutathione and catalase activity when compared with high-dose BPA-treated rats. Conclusion The present study provided clear evidence that SO possesses a promising protective activity against the cardiotoxic effects of BPA.

HYPOTHYROIDISM INCREASES EXPRESSION OF STERILE INFLAMMATION PROTEINS IN RAT HEART TISSUE.

In this study, we aimed to investigate the relationship between hypothyroidism and sterile inflammation in rat heart tissue. Groups; control group (fed with standard rat chow diet and tab water) and the hypothyroid group (fed with a standard rat chow diet and tap water containing 0.05% 6-n-propyl-2-thiouracil for 6-weeks). At the end of the experiment, histopathologic examination was performed. The T3, T4, TSH and myocardial malondialdehyde (MDA) measurements were performed with an ELISA kit. TUNEL assay was performed to demonstrate apoptosis. Sterile inflammation markers, caspase-1 and NLRP3, were investigated by immunohistochemistry and western blot. In histopathological examination, we observed leukocyte infiltration, myocardial atrophy, pyknotic nucleated cells and cytoplasmic vacuolization in hypothyroid group whereas the control group showed normal structure. MDA levels in myocardial tissue were significantly high in hypothyroid group when compared to the control group (P<0.05). Myocardial apoptosis increased in hypothyroid group when compared to the control group. NLRP3 and caspase-1 immunoreactivity was higher in the hypothyroid group. In ELISA results, we found significantly higher level of TSH and lower levels of T3 and T4 in hypothyroid group when compared to the control group. Hypothyroidism increased oxidative stress, and caused inflammatory alterations in cardiac tissue. In addition, our study also suggested that thyroid hormone deficiency would increase the amounts of cardiac NLRP3 and caspase-1 protein, which indicates that hypothyroidism exerts its destructive effects through sterile inflammation. Elucidation of sterile inflammation-associated pathways may produce promising results in the treatment of hypothyroidism-induced cardiac damage.

Fisetin, a plant flavonoid ameliorates doxorubicin-induced cardiotoxicity in experimental rats: the decisive role of caspase-3, COX-II, cTn-I, iNOs and TNF-α.

Doxorubicin (DOX) is a widely used anthracycline antibiotic for the management of carcinoma. However, it is associated with cardiotoxicity. Fisetin is a plant flavonoid reported to have anti-inflammatory and antiapoptotic potential. To evaluate the cardioprotective potential of fisetin in DOX-induced cardiotoxicity in experimental rats. Sprague-Dawley rats were pre-treated with either fisetin (10, 20 and 40mg/kg) or sitagliptin (10mg/kg, p.o.) for 7days. Cardiac toxicity was induced in rats (except the normal group) by doxorubicin (15mg/kg i.p.) on 8th day. Various behavioral, biochemical, molecular and histological parameters were assessed in cardiac tissue. DOX-induced alterations in electrocardiographic, hemodynamic and left ventricular function were significantly (p < 0.05) inhibited by fisetin (20 and 40mg/kg) treatment. Fisetin significantly decrease (p < 0.05) DOX-induced elevated serum CK-MB, LDH, AST, ALT and ALP levels. DOX-induced elevated cardiac oxido-nitrosative (SOD, GSH, MDA and NO) was significantly inhibited (p < 0.05) by fisetin. Up-regulated cardiac caspase-3, COX-II, cTn-I, iNOs, TNF-α, and IL-1β mRNA, as well as protein expressions were significantly decreased (p < 0.05) by fisetin treatment. It also significantly (p < 0.05) attenuated DOX-induced histopathological alterations in cardiac tissue. In conclusion, the fisetin exerts its cardioprotective potential against DOX-induced toxicity via inhibition of multiple pathways including oxidative stress (SOD, GSH, MDA and NO), inflammation (COX-II, TNF-α, and IL-1β), and apoptosis (Caspase-3). Therefore, fisetin can be considered as a potential cardioprotective agent during the management of carcinoma using doxorubicin anthracyclines.

Input of NAcGlc6SO3 epitopes (sulfotopes) present in Trypanosoma cruzi glycoproteins, and their specific antibodies, in the infection and immune pathogenesis of experimental Chagas disease

Background: Trypanosoma cruzi, the causative agent of Chagas disease contains a major antigen, cruzipain (Cz). The C-terminal domain (C-T) of this glycoprotein bears N-linked high mannose type sulfated oligosaccharide chains and is responsible for most antibodies in natural and experimental infections. Mice immunization with C-T has shown that sulfate moieties of Cz molecule are targets for specific immune responses and responsible for cardiac ultrastructural abnormalities in absence of infection. Methods & Materials: After the molecular characterization of these sufotopes, BALB/c mice were immunized with Cz/C-T, prior and after desulfation treatment, and with NAcGlc6SO3-BSA, to be further sublethally challenged with trypomastigotes to investigate whether they are involved in immunepathogenesis and/or infection of experimental Chagas disease. Results: C-T-immunized mice showed low IL-4 levels and elevated IFN-γ concentration by capture ELISA using C-T as stimulus and a cytokines profile compatible with a mixed response showing: Th2 tendency with excessively high IFNγ and raised IL-17 levels. By contrast, dC-T-immunized-mice presented undetectable IL-4 levels, low IFN-γ level and a cytokines profile like that of control but with a significantly elevated IL-10 value. In addition, ultrastructural cardiac alterations and main immunorecognition of fibrils and mitochondria were observed in C-T-immunized mice both confronted with polyclonal anti-Cz and myosin adsorbed anti-Cz sera. After sublethal challenge, elevated parasitaemias were observed. Mortality was 20 and 80% in C-T and dC-T immunized mice, respectively and mice from dC-T group that survived presented severe muscle alterations. BSA-NAcGlc6SO3-immunized mice mounted a predominant IgG1and IgG2b immune response followed by IgG2a, demonstrating the immunodominance of the sulfotope and a vigorous mice memory T cells response, similarly to C-T-immunized mice. After sublethal infection, mice immunized with the sulfotope displayed excessively elevated parasitemias, similar IFN-γ levels and significant lower mortality percentage than those from BSA-NAcGlc control group. Furthermore, mice treated by passive transference of sulfate-specific IgGs purified from sera of BSA-NAcGlc6SO3-immunized mice, exhibited ultrastructural alterations in cardiac tissue. After challenge, those treated with sulfate-specific IgGs presented higher parasitemias than controls Conclusion: Altogether, these findings have demonstrated that sulfotopes and their specific antibodies display a dual role, participating in the host-tissue immunopathogenicity of experimental Chagas disease and favoring the infection by T. cruzi.

Cardiac Depression in Pigs after Multiple Trauma \u2013 Characterization of Posttraumatic Structural and Functional Alterations

The purpose of this study was to define the relationship between cardiac depression and morphological and immunological alterations in cardiac tissue after multiple trauma. However, the mechanistic basis of depressed cardiac function after trauma is still elusive. In a porcine polytrauma model including blunt chest trauma, liver laceration, femur fracture and haemorrhage serial trans-thoracic echocardiography was performed and correlated with cellular cardiac injury as well as with the occurrence of extracellular histones in serum. Postmortem analysis of heart tissue was performed 72 h after trauma. Ejection fraction and shortening fraction of the left ventricle were significantly impaired between 4 and 27 h after trauma. H-FABP, troponin I and extracellular histones were elevated early after trauma and returned to baseline after 24 and 48 h, respectively. Furthermore, increased nitrotyrosine and Il-1β generation and apoptosis were identified in cardiac tissue after trauma. Main structural findings revealed alteration of connexin 43 (Cx43) and co-translocation of Cx43 and zonula occludens 1 to the cytosol, reduction of α-actinin and increase of desmin in cardiomyocytes after trauma. The cellular and subcellular events demonstrated in this report may for the first time explain molecular mechanisms associated with cardiac dysfunction after multiple trauma.

Experimental blunt chest trauma-induced myocardial inflammation and alteration of gap-junction protein connexin 43.

ObjectiveSevere blunt chest trauma in humans is associated with high mortality rates. Whereas lung tissue damage and lung inflammation after blunt chest trauma have extensively been investigated, the traumatic and posttraumatic effects on the heart remain poorly understood. Therefore, the purpose of this study was to define cardiac injury patterns in an experimental blunt chest trauma model in rats.MethodsExperimental blunt chest trauma was induced by a blast wave in rats, with subsequent analysis of its effects on the heart. The animals were subjected either to a sham or trauma procedure. Systemic markers for cardiac injury were determined after 24 h and 5 days. Postmortem analysis of heart tissue addressed structural injury and inflammation 24 h and 5 days after trauma.ResultsPlasma levels of extracellular histones were elevated 24 h and 5 days after blunt chest trauma compared to sham-treated animals. In the heart, up-regulation of interleukin-1β 24 h after trauma and increased myeloperoxidase activity 24 h and 5 days after trauma were accompanied by reduced complement C5a receptor-1 expression 24 h after trauma. Histological analysis revealed extravasation of erythrocytes and immunohistochemical analysis alteration of the pattern of the gap-junction protein connexin 43. Furthermore, a slight reduction of α-actinin and desmin expression in cardiac tissue was found after trauma together with a minor increase in sarcoplasmatic/endoplasmatic reticlulum calcium-ATPase (SERCA) expression.ConclusionsThe clinically highly relevant rat model of blast wave-induced blunt chest trauma is associated with cardiac inflammation and structural alterations in cardiac tissue.

Ameliorative effect of apelin on streptozotocin-induced diabetes and its associated cardiac hypertrophy

AimApelin, an adipocyte-derived factor, exhibited a number of cardioprotective properties; however, its effect in diabetes which is a major risk factor for cardiovascular disease (CVD) needs to be further studied. So this work was designed to evaluate the effect of apelin on diabetes and its associated cardiac hypertrophy with its possible underlying protective mechanisms. Experimental protocolThirty male adult Wistar rats were categorized into three groups, 10 rats each, normal control group: received standard food and water regime. Diabetic control group: received streptozotocin (STZ) at a dose of (55mg/kg, i.p., once) dissolved in citrate buffer (pH 4.5). Apelin-13 treated diabetic group: STZ diabetic rats received an intra peritoneal injection of apelin-13 at a dose of (100nmol/kg/day), and given daily for 8weeks. at the end of the experiment, oral glucose tolerance test (OGTT) was assayed, then rats were sacrificed and serum glucose, insulin, triglyceride (TG), total cholesterol, high density lipoprotein (HDL) cholesterol, serum lactate dehydrogenase (LDH) and serum creatine kinase – MB (CK-MB) were measured, together with cardiac hypertrophy index (CHI), left ventricular hypertrophy index (LVHI) and left ventricular protein and collagen content levels. Myocardial superoxide dismutase (SOD), catalase, reduced glutathione (GSH) and malondialdehyde (MDA) were determined in the myocardial tissue of experimental rats. ResultsTreatment with apelin-13 improved hyperglycemia and hyperlipidemia, and significantly protected against STZ-induced structural alterations in cardiac tissue, it also produced a significant reduction in MDA while it elevated the level of antioxidant enzymes in hearts of diabetic rats. ConclusionThis study suggested that apelin can ameliorate diabetes and its associated myocardial hypertrophy through mainly its anti diabetic, anti hyperlipidemic and anti oxidative stress properities.

In utero exposure of female CD-1 mice to AZT and/or 3TC: II. Persistence of functional alterations in cardiac tissue.

To delineate temporal changes in the integrity and function of mitochondria/cardiomyocytes in hearts from mice exposed in utero to commonly used nucleoside analogs (NRTIs), CD-1 mice were exposed in utero to 80 mg AZT/kg, 40 mg 3TC/kg, 80 mg AZT/kg plus 40 mg 3TC/kg, or vehicle alone during days 12-18 of gestation and hearts from female mouse offspring were examined at 13 and 26 weeks postpartum. Alterations in cardiac mitochondrial DNA (mtDNA) content, oxidative phosphorylation (OXPHOS) enzyme activities, mtDNA mutations, and echocardiography of NRTI-exposed mice were assessed and compared with findings in vehicle-exposed control mice. A hybrid capture-chemiluminescence assay showed significant twofold increases in mtDNA levels in hearts from AZT- and AZT/3TC-exposed mice at 13 and 26 weeks postpartum, consistent with near doubling in mitochondrial numbers over time compared with vehicle-exposed mice. Echocardiographic measurements at 13 and 26 weeks postpartum indicated progressive thinning of the left ventricular posterior wall in NRTI-exposed mice, relative to controls, with differences becoming statistically significant by 26 weeks. Overall, progressive functional changes occurred in mouse mitochondria and cardiac tissue several months after in utero NRTI exposures; AZT and 3TC acted in concert to cause additive cardiotoxic effects of AZT/3TC compared with either drug alone.

Rapid pacing of embryoid bodies impairs mitochondrial ATP synthesis by a calcium-dependent mechanism—A model of in vitro differentiated cardiomyocytes to study molecular effects of tachycardia

Tachycardia may cause substantial molecular and ultrastructural alterations in cardiac tissue. The underlying pathophysiology has not been fully explored. The purpose of this study was (I) to validate a three-dimensional in vitro pacing model, (II) to examine the effect of rapid pacing on mitochondrial function in intact cells, and (III) to evaluate the involvement of L-type-channel-mediated calcium influx in alterations of mitochondria in cardiomyocytes during rapid pacing. In vitro differentiated cardiomyocytes from P19 cells that formed embryoid bodies were paced for 24 h with 0.6 and 2.0 Hz. Pacing at 2.0 Hz increased mRNA expression and phosphorylation of ERK1/2 and caused cellular hypertrophy, indicated by increased protein/DNA ratio, and oxidative stress measured as loss of cellular thiols. Rapid pacing additionally provoked structural alterations of mitochondria. All these changes are known to occur in vivo during atrial fibrillation. The structural alterations of mitochondria were accompanied by limitation of ATP production as evidenced by decreased endogenous respiration in combination with decreased ATP levels in intact cells. Inhibition of calcium inward current with verapamil protected against hypertrophic response and oxidative stress. Verapamil ameliorated morphological changes and dysfunction of mitochondria. In conclusion, rapid pacing-dependent changes in calcium inward current via L-type channels mediate both oxidative stress and mitochondrial dysfunction. The in vitro pacing model presented here reflects changes occurring during tachycardia and, thus, allows functional analyses of the signaling pathways involved.