metallothionein and Heart-Diseases

The Metallothionein (MT) is a protein which has several interesting biological effects and has been demonstrated increase focus on the role of MT in various biological systems in the past three decades. The studies on the role of MT were limited with few areas like apoptosis and antioxidants in selected organs even fifty years after its discovery. Now acknowledge the exploration of various isoforms of MT such as MT-I, MT-II, MT-III and MT-IV and other isoforms in various biological systems.Strong evidence exists that MT modulates complex diseases and the immune system in the body but the primary function of MT still remains unknown. This review's main objective is to explore the capability to specifically manipulate MT levels in cells and in animals to provide answers regarding how MT could impact those complex disease scenarios.The experimental result mentioned in this review related among MT, zinc, cadmium, diabetic, heart disease, bone retardation, neuro toxicity, kidney dysfunction, cancer, and brain suggest novel method for exploration and contribute significantly to the growing scientist to research further in this field.

Topics: Animals; Bone Diseases, Developmental; Central Nervous System; Diabetes Mellitus; Heart Diseases; Humans; Kidney Diseases; Metallothionein; Neoplasms; Oxidative Stress; Protein Isoforms

Anthracycline cardiotoxicity is related to oxidative stress generated from the metabolism of anthracyclines in the heart. Studies using transgenic mice with high levels of antioxidants such as catalase or metallothionein (MT) specifically in the heart have demonstrated that elevation of cardiac antioxidant defense leads to intervention of anthracycline cardiotoxicity. MT protection against anthracycline-induced cardiac toxicity is related to its anti-apoptotic effect by inhibiting both p38-MAPK-mediated and mitochondrial cytochrome c-release-mediated apoptotic signaling. The anti-apoptotic effect of MT is closely related to its antioxidant action, which involves regulation of zinc homeostasis by the MT redox cycle. MT interferes with oxidant-mediated detrimental process through at least in part zinc release and zinc transfers directly from MT to acceptor proteins. In addition, MT posttranslationally modulates critical proteins involved in mitochondrial respiration and energy metabolism. All of these processes constitute the mechanisms by which MT protects from anthracycline cardiotoxicity.

Topics: Animals; Anthracyclines; Antibiotics, Antineoplastic; Antioxidants; Cardiotonic Agents; Heart Diseases; Humans; Metallothionein; Oxidation-Reduction; Protein Processing, Post-Translational; Zinc

We previously demonstrated that metallothionein (MT)-mediated protection from diabetes-induced pathological changes in cardiac tissues is related to suppression of superoxide generation and protein nitration. The present study investigated which diabetes-nitrated protein(s) mediate the development of these pathological changes by identifying the panel of nitrated proteins present in diabetic hearts of wild-type (WT) mice and not in those of cardiac-specific MT-overexpressing transgenic (MT-TG) mice. At 2, 4, 8, and 16 wk after streptozotocin induction of diabetes, histopathological examination of the WT and MT-TG diabetic hearts revealed cardiac structure derangement and remodeling, significantly increased superoxide generation, and 3-nitrotyrosine accumulation. A nitrated protein of 58 kDa, succinyl-CoA:3-ketoacid CoA transferase-1 (SCOT), was identified by mass spectrometry. Although total SCOT expression was not significantly different between the two types of mice, the diabetic WT hearts showed significantly increased nitration content and dramatically decreased catalyzing activity of SCOT. Although SCOT nitration sites were identified at Tyr(76), Tyr(117), Tyr(135), Tyr(226), Tyr(368), and Trp(374), only Tyr(76) and Trp(374) were found to be located in the active site by three-dimensional structure modeling. However, only Trp(374) showed a significantly different nitration level between the WT and MT-TG diabetic hearts. These results suggest that MT prevention of diabetes-induced pathological changes in cardiac tissues is most likely mediated by suppression of SCOT nitration at Trp(374).

Topics: Animals; Coenzyme A-Transferases; Diabetes Mellitus, Experimental; Disease Models, Animal; Energy Metabolism; Heart Diseases; Male; Metallothionein; Mice; Mice, Inbred Strains; Mice, Transgenic; Myocardium; Nitrogen; Protein Structure, Tertiary; Superoxides; Tryptophan; Tyrosine

Low-ambient temperature environment exposure increased the risk of cardiovascular morbidity and mortality, although the underlying mechanism remains unclear. This study was designed to examine the impact of cardiac overexpression of metallothionein, a cysteine-rich heavy metal scavenger, on low temperature (4°C)-induced changes in myocardial function and the underlying mechanism involved, with a focus on autophagy. Cold exposure (4°C for 3 wk) promoted oxidative stress and protein damage, increased left ventricular end-systolic and -diastolic diameter, and suppressed fractional shortening and whole heart contractility, the effects of which were significantly attenuated or ablated by metallothionein. Levels of the autophagy markers LC3B-II, beclin-1, and Atg7 were significantly upregulated with unchanged autophagy adaptor protein p62. Fluorescent immunohistochemistry revealed abundant LC3B puncta in cold temperature-exposed mouse hearts. Coimmunoprecipitation revealed increased dissociation between Bcl2 and Beclin-1. Cold exposure reduced phosphorylation of the autophagy inhibitory signaling molecules Akt and mTOR, increased ULK1 phosphorylation, and dampened eNOS phosphorylation (without changes in their total protein expression). These cold exposure-induced changes in myocardial function, autophagy, and autophagy signaling cascades were significantly alleviated or mitigated by metallothionein. Inhibition of autophagy using 3-methyladenine in vivo reversed cold exposure-induced cardiomyocyte contractile defects. Cold exposure-induced cardiomyocyte dysfunction was attenuated by the antioxidant N-acetylcysteine and the lysosomal inhibitor bafilomycin A1. Collectively, these findings suggest that metallothionein protects against cold exposure-induced cardiac anomalies possibly through attenuation of cardiac autophagy.

Topics: Animals; Autophagy; Cardiotonic Agents; Cold Temperature; Free Radical Scavengers; Heart Diseases; Hypothermia; Male; Metallothionein; Metals, Heavy; Mice; Mice, Transgenic; Myocardial Contraction; Myocytes, Cardiac; Oxidative Stress; Severity of Illness Index

Present study evaluates cardioprotective role of melatonin (Mel), alpha lipoic acid (ALA), a combination of melatonin and alpha lipoic acid (Mel + ALA) against cadmium (Cd)-induced oxidative damage. Female albino rats were subjected to 15-day exposure to Cd (5.12 mg/kg bw) alone or treated with ML (10 mg/kg bw) + ALA (25 mg/kg bw) simultaneously. Plasma markers of cardiac damage, cardiac free radical generation, lipid peroxidation, endogenous antioxidant status, cadmium load, metallothionein induction, and histopathology were evaluated in various experimental groups. Combination of Mel + ALA significantly prevented leakage of marker enzymes of cardiac damage, changes in cardiac free radical generation, endogenous antioxidants, antioxidant status, structural alterations and augmented the degree of metallothionein (MT) induction. The results demonstrate that ML + ALA co-administration effectively protected against Cd-induced cardiac oxidative damage.

Topics: Animals; Antioxidants; Ascorbic Acid; Biomarkers; Cadmium Chloride; Drug Synergism; Drug Therapy, Combination; Enzymes; Female; Glutathione; Heart Diseases; Hydrogen Peroxide; Hydroxyl Radical; Lipid Peroxidation; Malondialdehyde; Melatonin; Metallothionein; Myocardium; Oxidative Stress; Rats; Thioctic Acid; Vitamin E

Diabetic cardiomyopathy contributes to high morbidity and mortality in diabetic populations. It is manifested by compromised ventricular contraction and prolonged relaxation attributable to multiple causative factors including oxidative stress. This study was designed to examine the effect of cardiac overexpression of the heavy metal scavenger metallothionein (MT) on cardiac contractile function, intracellular Ca(2+) cycling proteins, stress-activated signaling molecules and the myosin heavy chain (MHC) isozyme in diabetes. Adult male wild-type (FVB) and MT transgenic mice were made diabetic by a single injection of streptozotocin (STZ). Contractile properties were evaluated in cardiomyocytes including peak shortening (PS), time-to-PS (TPS), time-to-relengthening (TR(90)), maximal velocity of shortening/relengthening (+/-dL/dt) and intracellular Ca(2+) fluorescence. Diabetes significantly depressed PS, +/-dL/dt, prolonged TPS, TR(90) and intracellular Ca(2+) clearing, elevated resting intracellular Ca(2+), reduced caffeine-induced sarcoplasmic reticulum Ca(2+) release and dampened stress tolerance at high stimulus frequencies. MT itself exhibited little effect on myocyte mechanics but it significantly alleviated STZ-induced myocyte contractile dysfunctions. Diabetes enhanced expression of the AT(1) receptor, phospholamban, the p47(phox) NADPH oxidase subunit and poly(ADP-ribose) polymerase (PARP), depressed the level of SERCA2a, Na(+)-Ca(2+) exchanger and triggered a beta-MHC isozyme switch. All of these STZ-induced alterations with the exception of depressed SERCA2a and enhanced phospholamban were reconciled by MT. Collectively, these data suggest a beneficial effect of MT in the therapeutics of diabetic cardiomyopathy, possibly through a mechanism related to NADPH oxidase, PARP and MHC isozyme switch.

Topics: Animals; Calcium; Cations, Divalent; Diabetes Mellitus, Experimental; Heart Diseases; Isoenzymes; Male; Metallothionein; Mice; Mice, Transgenic; Muscle Cells; Myosin Heavy Chains; NADPH Oxidases; Oxidative Stress; Poly(ADP-ribose) Polymerases; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Streptozocin

The mechanisms of metallothionein prevention of diabetic cardiomyopathy are largely unknown. The present study was performed to test whether inhibition of nitrosative damage is involved in metallothionein prevention of diabetic cardiomyopathy. Cardiac-specific metallothionein-overexpressing transgenic (MT-TG) mice and wild-type littermate controls were treated with streptozotocin (STZ) by a single intraperitoneal injection, and both developed diabetes. However, the development of diabetic cardiomyopathy, revealed by histopathological and ultrastructural examination, serum creatine phosphokinase, and cardiac hemodynamic analysis, was significantly observed only in the wild-type, but not in MT-TG, diabetic mice 2 weeks and 6 months after STZ treatment. Formations of superoxide and 3-nitrotyrosine (3-NT), a marker for peroxynitrite-induced protein damage, were detected only in the heart of wild-type diabetic mice. Furthermore, primary cultures of cardiomyocytes from wild-type and MT-TG mice were exposed to lipopolysaccharide/tumor necrosis factor-alpha for generating intracellular peroxynitrite. Increases in 3-NT formation and cytotoxicity were observed in wild-type, but not in MT-TG, cardiomyocytes. Either urate, a peroxynitrite-specific scavenger, or Mn(111) tetrakis 1-methyl 4-pyridyl porphyrin pentachloride (MnTMPyP), a superoxide dismutase mimic, significantly inhibited the formation of 3-NT along with a significant prevention of cytotoxicity. These results thus suggest that metallothionein prevention of diabetic cardiomyopathy is mediated, at least in part, by suppression of superoxide generation and associated nitrosative damage.

Topics: Animals; Cardiomyopathies; Diabetes Complications; Gene Expression; Heart Diseases; Male; Metallothionein; Mice; Mice, Transgenic; Nitrosation; Superoxides; Tyrosine

Metallothionein (MT) may provide protection against doxorubicin-induced heart damage. To test this hypothesis, a heart-specific promoter was used to drive the expression of human MT-IIa gene in transgenic mice. Four healthy transgenic mouse lines were produced. Cardiac MT was constitutively overexpressed from 10- to 130-fold higher than normal. The MT concentration was not altered in liver, kidneys, lungs, or skeletal muscles. Other antioxidant components including glutathione, glutathione peroxidase, glutathione reductase, catalase, and superoxide dismutase were not altered in the MT-overexpressing heart. Mice (7-wk-old) from transgenic lines expressing MT activity 10- or 130-fold higher than normal and from nontransgenic controls were treated intraperitoneally with doxorubicin at a single dose of 20 mg/kg, and were killed on the 4th day after treatment. As compared to normal controls, transgenic mice exhibited a significant resistance to in vivo doxorubicin-induced cardiac morphological changes, and the increase in serum creatine phosphokinase activity. Atria isolated from transgenic mice and treated with doxorubicin in tissue bath was also more resistant to functional damage induced by this drug. The results provide direct evidence for the role of MT in cardioprotection against doxorubicin toxicity.

Topics: Animals; Catalase; Creatine Kinase; Doxorubicin; Female; Glutathione; Glutathione Peroxidase; Glutathione Reductase; Heart Diseases; Humans; In Vitro Techniques; Male; Metallothionein; Mice; Mice, Transgenic; Microscopy, Electron; Myocardial Contraction; Myocardium; Promoter Regions, Genetic; RNA, Messenger; Superoxide Dismutase; Tissue Distribution