metallothionein and Myocardial-Infarction

Topics: Adipokines; Animals; Apoptosis; Cell Movement; Cell Proliferation; Disease Models, Animal; Fibrosis; Heart; Hydrogen Peroxide; MAP Kinase Signaling System; Matrix Metalloproteinase 9; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Metallothionein; Mice; Mice, Inbred C57BL; Myocardial Infarction; Myocardium; Signal Transduction; Superoxide Dismutase; Tumor Necrosis Factors; Ventricular Function, Left

Aims. Repetitive brief ischemia and reperfusion (I/R) is associated with left ventricular dysfunction during development of ischemic cardiomyopathy. We investigated the role of zinc-donor proteins metallothionein MT1 and MT2 in a closed-chest murine model of I/R. Methods. Daily 15-minute LAD-occlusion was performed for 1, 3, and 7 days in SV129 (WT)- and MT1/2 knockout (MT(-/-))-mice (n = 8-10/group). Hearts were examined with M-mode echocardiography and processed for histological and mRNA studies. Results. Expression of MT1/2 mRNA was transiently induced during repetitive I/R in WT-mice, accompanied by a transient inflammation, leading to interstitial fibrosis with left ventricular dysfunction without infarction. In contrast, MT(-/-)-hearts presented with enhanced apoptosis and small infarctions leading to impaired global and regional pump function. Molecular analysis revealed maladaptation of myosin heavy chain isoforms and antioxidative enzymes in MT1/2(-/-)-hearts. Despite their postponed chemokine induction we found a higher total neutrophil density and macrophage infiltration in small infarctions in MT(-/-)-hearts. Subsequently, higher expression of osteopontin 1 and tenascin C was associated with increased myofibroblast density resulting in predominately nonreversible fibrosis and adverse remodeling in MT1/2(-/-)-hearts. Conclusion. Cardioprotective effects of MT1/2 seem to be exerted via modulation of contractile elements, antioxidative enzymes, inflammatory response, and myocardial remodeling.

Topics: Animals; Apoptosis; Cardiomyopathies; Disease Models, Animal; Echocardiography; Metallothionein; Mice; Mice, Knockout; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Osteopontin; Tenascin

Activation of cardiac STAT3 by IL-6 cytokine family contributes to cardioprotection. Previously, we demonstrated that IL-11, an IL-6 cytokine family, has the therapeutic potential to prevent adverse cardiac remodeling after myocardial infarction; however, it remains to be elucidated whether IL-11 exhibits postconditioning effects. To address the possibility that IL-11 treatment improves clinical outcome of recanalization therapy against acute myocardial infarction, we examined its postconditioning effects on ischemia/reperfusion (I/R) injury. C57BL/6 mice were exposed to ischemia (30 min) and reperfusion (24 h), and IL-11 was intravenously administered at the start of reperfusion. I/R injury mediated the activation of STAT3, which was enhanced by IL-11 administration. IL-11 treatment reduced I/R injury, analyzed by triphenyl tetrazolium chloride staining [PBS, 46.7 ± 14.4%; IL-11 (20 μg/kg), 28.6 ± 7.5% in the ratio of infarct to risk area]. Moreover, echocardiographic and hemodynamic analyses clarified that IL-11 treatment preserved cardiac function after I/R. Terminal deoxynucleotide transferase-mediated dUTP nick-end labeling staining revealed that IL-11 reduced the frequency of apoptotic cardiomyocytes after I/R. Interestingly, IL-11 reduced superoxide production assessed by in situ dihydroethidium fluorescence analysis, accompanied by the increased expression of metallothionein 1 and 2, reactive oxygen species (ROS) scavengers. Importantly, with the use of cardiac-specific STAT3 conditional knockout (STAT3 CKO) mice, it was revealed that cardiac-specific ablation of STAT3 abrogated IL-11-mediated attenuation of I/R injury. Finally, IL-11 failed to suppress the ROS production after I/R in STAT3 CKO mice. IL-11 administration exhibits the postconditioning effects through cardiac STAT3 activation, suggesting that IL-11 has the clinical therapeutic potential to prevent I/R injury in heart.

Topics: Animals; Animals, Newborn; Apoptosis; Cardiotonic Agents; Cells, Cultured; Cytoprotection; Disease Models, Animal; Dose-Response Relationship, Drug; Gene Expression Regulation; Hemodynamics; Humans; Injections, Intravenous; Interleukin-11; Metallothionein; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Oxidative Stress; Phosphorylation; Rats; Rats, Wistar; Reactive Oxygen Species; RNA Interference; Signal Transduction; STAT3 Transcription Factor; Time Factors; Transfection; Ventricular Function, Left; Ventricular Pressure

Previous studies using a cardiac-specific metallothionein (MT)-overexpressing transgenic mouse model have demonstrated that MT inhibits ischemia/reperfusion-induced myocardial injury. The present study was undertaken to test the hypothesis that the MT inhibition is associated with suppression of apoptosis mediated by mitochondrial cytochrome c release and caspase-3 activation. An open-chest coronary artery occlusion and reperfusion procedure to produce ischemia/reperfusion-induced left ventricle infarction was used in MT-overexpressing transgenic mice and non-transgenic controls. After 30 minutes of ischemia, the left ventricle was reperfused to allow blood flow through the previously occluded coronary artery bed. Myocardial infarction produced after reperfusion for 4 hours was significantly reduced in the MT transgenic mice. This inhibition correlated with the antiapoptotic effect of MT, as determined by a terminal deoxynucleotidyl transferase-mediated deoxyuridine 5-triphosphate nick-end labeling assay, mitochondrial cytochrome c release and caspase-3 activation. Ischemia/reperfusion-induced lipid peroxidation was also significantly inhibited in the MT-transgenic heart. Dimethylsulfoxide, a chemical scavenger for reactive oxygen species, was used to confirm the antioxidant effect of MT and found to suppress myocardial infarction and lipid peroxidation just as MT did. This study thus demonstrates that MT suppresses ischemia/reperfusion-induced myocardial apoptosis through, at least in part, the inhibition of cytochrome c-mediated caspase-3 activation pathway. The antiapoptotic effect of MT likely results from the suppression of oxidative stress and correlates with the inhibition of myocardial infarction.

Topics: Animals; Apoptosis; Caspase 3; Caspases; Cytochrome c Group; Dimethyl Sulfoxide; Enzyme Activation; Free Radical Scavengers; Heart; Lipid Peroxidation; Metallothionein; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Rats

Oxidative stress is believed to play a major role in ischemia-reperfusion injury to the heart. Metallothionein (MT), a potential free radical scavenger, may function in cardiac protection against ischemia-reperfusion damage. To test this hypothesis, a specific cardiac MT-overexpressing transgenic mouse model was used. The hearts isolated from these animals were subjected to 50 min of warm (37 degrees C) zero-flow ischemia followed by 60- or 90-min reflow. Compared with the nontransgenic controls, the transgenic mouse hearts with MT concentrations approximately 10-fold higher than normal showed significantly improved recovery of contractile force postischemia (69.2 +/- 4.2 vs. 26.0 +/- 6.0% at the end of 60-min reperfusion, P < 0.01). Efflux of creatine kinase from these transgenic hearts was reduced by more than 50% (P < 0.01). In addition, the zone of infarction induced by ischemia-reperfusion at the end of 90-min reperfusion was suppressed by approximately 40% (P < 0.01) in the transgenic hearts. The results strongly indicate that MT provides protection against ischemia-reperfusion-induced heart injury.

Topics: Animals; Heart; In Vitro Techniques; Metallothionein; Mice; Mice, Inbred Strains; Mice, Transgenic; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury

Topics: Adult; Aged; Copper; Female; Humans; Male; Metallothionein; Middle Aged; Myocardial Infarction; Zinc

To study whether metallothionein (MT) is an OH scavenger and plays a protective role in cardiac ischemic/reperfusion injury. MT involves in the delayed protection 24 hr after preconditioning (PC).. MT contents in myocardium or cultured cardiomyocytes are assayed at the 0 hr, 12 hr, and 24 hr after PC on the model of rabbit heart in situ or that of the cultured cardiomyocytes. The myocardial infarct size, LDH release, cell viability, and the content of cellular MDA were measured with or without the intervention of PD098059, the inhibitor of mitogen-activated protein kinase in the models before PC and different time intervals after PC.. The MT contents were increased significantly at 2 hr (1406.2 +/- 112.2 vs 129.9 +/- 10.4 pmol/mg Pr., P < 0.01, in cardiomyocytes) and 24 hr (1032.7 +/- 199.1 vs 129.9 +/- 10.4 pmol/mg Pr., P < 0.01, in cardiomyocytes; 62.1 +/- 12.6 vs 27.2 +/- 3.7 pmol/mg Pr., P < 0.01, in myocardium) after PC compared with those in normal group. The infarct sizes (13.2 +/- 3.6% vs 32.3 +/- 5.7%, P < 0.05) and the rise of LDH release in plasma (1944 +/- 256 vs 2826 +/- 239 IU/L, P < 0.05) were greatly decreased in preconditioned myocardium after a long time ischemia-reperfusion than those in the unpreconditioned. Compared with the cardiomyocytes unconditioned, the number of viable cell (71.0 +/- 1.6 vs 48.2 +/- 2.2%, P < 0.01) was greatly increased, the cellular MDA contents (33.5 +/- 12.8 vs 103.5 +/- 15.0 nmol/mg Pr., P < 0.01) and the LDH release (850.0 +/- 139.1 vs 1552.0 +/- 102.6 IU/L, P < 0.01) were dramatically decreased in preconditioned ones. All the delayed protection at 24 hr after PC were completely disappeared with the inhibition of MT's production with PD098059 (P > 0.05).. The myocardium or cardiomyocytes at 24 hr after PC are offered more capacity to tolerate the I/R damage, and MT involves in the delayed protection.

Topics: Animals; Cells, Cultured; Ischemic Preconditioning, Myocardial; Male; Metallothionein; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Rabbits

The level of plasma endothelin (ET) was studied in 40 cases with acute myocardial infarction (AMI) with radioimmunoassay. The results showed that plasma ET level reached its peak value (46.01 +/- 1.64 pg/ml) immediately after AMI attack and dropped down (39.37 +/- 0.47 pg/ml) on the first day; The value was still high (15.56 +/- 1.40 pg/ml) on the twenty-eight day: this was significant higher than that in control group (6.35 +/- 0.44 pg/ml, P < 0.001). It was found that height of plasma ET level was closely correlated with severity of myocardial damage and degree of cardiac insufficiency. In order to evaluate the pathogenic role of ET in AMI, the effect of ET-antiserum on myocardial infarction (MI) was investigated on infarct model produced by ligature of left anterior descending coronary artery in rats. The results showed that plasma ET levels elevated significantly in rats with MI (8.4 +/- 1.0, sham 3.1 +/- 0.2 pg/ml, P < 0.01) and ET-antiserum administration dramatically decreased plasma ET level 65% (P < 0.01), lowered plasma content of lipid peroxide 27% (P < 0.01) and reduced infarct size 48% (P < 0.01). It is suggested that ET is an important factor which contributes to the pathogenesis of MI. Limb ischemia and reperfusion study was carried out in rats also. Metallothionein (MT) was found to antagonize markedly ET-induced vasoconstriction and lower the release of ET stimulated by angiotensin II in a dose-dependent manner. It is suggested that under certain pathological conditions MT may exert its injury--resistant and cell protective action.

Topics: Adult; Aged; Aged, 80 and over; Animals; Endothelins; Female; Humans; L-Lactate Dehydrogenase; Male; Malondialdehyde; Metallothionein; Middle Aged; Myocardial Infarction; Rats; Rats, Wistar

The amounts of myocardial metallothionein (MT) and heavy metal (Zn, Cu) levels during the early stage of the experimental myocardial infarction model induced by isoproterenol (Isp) administration were measured by an atomic absorption spectrophotometry. MT was measured by the Cd-hem method. Myocardial infarction was induced by the administration of 75 mg/kg i.p. of Isp to rats weighing 270 +/- 10 g. Thirty minutes after Isp injection, Zn and Cu levels began to decrease and 12 h later, reached the minimal values compared with the control value. The level of MT began to increase 3 h after the Isp injection and reached the maximal value at 12 h, although MT remained undetectable in the control myocardial tissue by the Cd-hem method. MT levels in the liver increased and total Zn and Cu were elevated compared with the control value 12 h after Isp administration. These results suggest that MT is produced in the myocardium after Isp administration, and that the roles of MT in the heart and the liver are different. It was thought that a rise in MT was induced for the protection of the myocardial cells to injury.

Topics: Animals; Copper; Isoproterenol; Male; Metallothionein; Myocardial Infarction; Myocardium; Rats; Rats, Wistar; Zinc

Metallothionein (MT) is an important endogenous anti-injury substance involved in the defensive system. In myocardial infarction model produced by left coronary artery occlusion in-rat, the content of left ventricular myocardial MT was significantly increased to a maximum on 4th day by 6-fold compared with preoperative value, and the content of hepatic MT increased by 3.5-fold on the 2nd day. During the whole experimental period (seven days) the MT content in heart and liver was significantly higher than those in the pre-operation period (P less than 0.01). Pretreatment with reserpine did not alter the dynamic changes of cardiac and liver MT content during myocardial infarction. The above results suggest that this increase in tissue MT is not influenced by catecholamine.

Topics: Animals; Liver; Male; Metallothionein; Myocardial Infarction; Myocardium; Rats; Rats, Inbred Strains; Reserpine