Role Of Metallothionein Research Articles

Zn tolerance of novel Colocasia esculenta metallothionein and its domains in Escherichia coli and tobacco

Contrary to extensive researches on the roles of metallothioneins (MTs) in metal tolerance of animals, the roles of plant MTs in metal tolerance are largely under investigation. In this study, we evaluated the functional role of type 2 MT from Colocasia esculenta (CeMT2b) in Zn tolerance of tobacco and E. coli cells. Under Zn-stress conditions, transgenic tobacco overexpressing CeMT2b displayed much better seedling growth, a significant decrease in the levels of H(2)O(2) and an increase in Zn accumulation compared with the wild type. Overexpression of CeMT2b in E. coli greatly enhanced Zn tolerance and Zn accumulation under Zn stresses compared with control cells. CeMT2b bound 5.38±0.29 atoms of Zn per protein. To identify a structural domain of CeMT2b for Zn binding, we investigated the growth of E. coli expressing each of the N-terminal, C-terminal, and central linker domains or a CNC motif deletion from the C-terminus of full-length CeMT2b. The results showed that the CNC motif is required for Zn tolerance, and the N-terminal domain is more effective in Zn tolerance than the C-terminal domain. Taken together, our results provide direct evidence for functional contributions of CeMT2b in Zn tolerance of tobacco and E. coli cells.

Survival Study of Metallothionein-1 Transgenic Mice and Respective Controls (C57BL/6J): Influence of a Zinc-Enriched Environment

The role of metallothioneins (MTs) in aging is not completely understood. Several studies have shown evidence that these proteins could represent a defense system against oxidative damage, but survival studies on mice overexpressing MTs are poor. Here we describe a survival study performed on old MT-1-overexpressing mice (MT-TG) and their respective controls (C57BL/6J) fed a standard or zinc (Zn)-supplemented diet. MT-TG mice had significantly increased survival compared with control. Zn supplementation affects the survival curves of MT-TG and C57BL/6J mice differently. This study poses the basis for intervention based on gene therapy with MTs to enhance the health span of laboratory mice.

Expression of Metallothioneins in Cutaneous Squamous Cell Carcinoma and Actinic Keratosis

Metallothioneins (MT) are low-molecular weight proteins implicated in heavy metal detoxification, zinc and cooper homeostasis and cell protection against free radicals. In variety of cancers MT-overexpression was shown, but there are just a few studies on the role of MT in skin carcinogenesis. Current study was undertaken to evaluate MT and Ki-67 expression in pre-cancerous skin lesions as well as in fully developed skin cancers. 73 squamous cell carcinomas (SCC), 23 actinic keratoses (AK) and 20 normal skin samples were included in the study. In obtained paraffin sections immunohistochemical reactions were performed. MT-expression in SCC (mean 2.89 ± 1.83) was significantly higher than in AK (mean 1.69 ± 1.26)(p = 0.006) and higher than in normal skin (mean 2 ± 0.79) (p = 0.0075). The MT-expression positively correlated with Ki-67 expression (R = 0.28; p = 0.017) in SCC and in AK (R = 0.49; p = 0.018). Various clinico-pathological variables, e.g. morphology, size of lesions and the depth of neoplastic infiltration were not associated to MT-expression in both SCC and AK. The grade of histological differentiation of SCC correlated positively with Ki-67 antigen (p < 0.001) and did not correlate with MT-expression (p = 0.06). Ki-67 expression was higher in SCC and in AK than in healthy skin (p = 0,003). In SCC and in AK expression of Ki-67 antigen correlated positively with MT-expression (respectively p = 0.017 and p = 0.018). MT may serve as a good markers of proliferation in SCC and AK. MT-overexpression in SCC may suggest a potential role of MT in skin carcinogenesis.

Health effects of low-level cadmium intake and the role of metallothionein on cadmium transport from mother rats to fetus

Female Wistar rats were given Cd (as CdCl(2)) at a dose of 0, 1, 2, and 5 mgCd/kg/day by gastric tube daily for 6 consecutive days each week for 10 weeks. After the birth, newborn rats were sacrificed on day 1 and at 4 weeks. Mother rats were sacrificed after 4 weeks of lactation The concentrations of Cd in uterus and placenta, and metallothionein (MT) in the uterus of mother rats were determined. The concentrations of Cd in kidney and liver of newborn rats were also determined. Expression of iso-MT genes (I, II, and III) in the uterus of mother rats was measured using RT-PCR. The Cd concentration in the liver of newborn rats at the first day after birth was higher than in the kidney, while the concentration in the kidney of newborn rats at the fourth week after the birth was significantly higher than in the liver. The uterine MT concentration increased with accumulation of Cd; however, the MT concentration did not increase enough to prevent Cd transport to the fetus. On the other hand, it was considered that more Cd was transported as the chemical form of nonMT-Cd from mother rat, and accumulated in the liver rather than kidney of the fetus. Based on analyses of the Cd distribution in the liver and kidney of newborn rats, we speculate that MT in the uterus and placenta does not play a significant role in preventing Cd transport through the placenta from the uterus to the fetus.

Role of metallothionein and metal transporters on cadmium transport from mother to fetus in rat

Role of metallothionein and metal transporters on cadmium transport from mother to fetus in rat

Overexpression of Metallothionein I/II: A New Feature of Thyroid Follicular Cells in Graves' Disease

One salient feature of autoimmune thyroid disease is the inappropriate expression of human leukocyte antigen (HLA) class II molecules by thyroid follicular cells. Metallothioneins (MT) are small proteins induced by tissue stress that can contribute to restoring homeostasis of tissue inflammation and have been found to be increased in a transcriptomic analysis of Graves' disease (GD) glands. To assess the role of MT in the pathogenesis of GD, we analyzed MT-I and -II expression and distribution in GD-affected thyroid glands (n = 14) compared with other thyroid diseases (n = 20) and normal thyroid glands (n = 5). Two-color indirect immunofluorescence and semiquantitative morphometry were applied. The relationship between MT and HLA class II expression was analyzed by their degree of colocalization in GD sections, and in vitro induction kinetics and expression of these molecules on the HT93 thyroid cell line were compared by quantitative RT-PCR and flow cytometry using interferon-γ and zinc as stimuli. MT were clearly overexpressed in nine of 14 GD glands. MT expression distribution in GD was almost reciprocal to that of HLA class II. In vitro analysis of MT and HLA class II demonstrated that MT is induced more slowly and at a lower level than HLA. Moreover, the main MT inducer, zinc, reduces interferon-γ-induced class II expression. These findings show that MT and HLA class II play very different roles in the autoimmune process by affecting the thyroid gland, thereby pointing to the possible role of MT as a marker of cell stress and homeostasis restoration in GD.

The role of metallothionein and serum albumin as native metal-abeta attenuating compounds

The role of metallothionein and serum albumin as native metal-abeta attenuating compounds

A Review of Metallothionein Isoforms and their Role in Pathophysiology

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.

Metal Release from and Sequestration by Metallothioneins Monitored by Electrochemistry and SPR

Due to the high affinity of metallothioneins (MTs) toward various transition metal ions, MTs play an important role in regulation of essential metals, detoxification of heavy metals, and scavenging of free radicals. In this review, we focus on the recent development on the metal release from and sequestration by MTs characterized by electrochemistry and surface plasmon resonance (SPR). The investigation of metal release and coordination processes is of great significance in illustrating the intriguing role of MTs in environmental toxicology.

Abstract 909: Activation of NF-κB and its downstream targets play a key role in the dramatic induction of hepatocarcinogenesis in metallothionein null mice

Abstract Hepatocellular Carcinoma (HCC) is one of the most prevalent cancers in the world and the third leading cause of cancer-related death. Although hepatitis C and fatty liver disease appear to be the main risk factors in most western countries other factors including alcohol, tobacco, diabetes, and other metabolic disorders can also increase the likelihood of HCC development. HCC is believed to develop through a tumor promoting mechanism involving inflammation and oxidative stress. We have previously shown that metallothionein (MT), a ubiquitously expressed free radical scavenger, is dramatically downregulated in human and rodent HCCs. To test the hypothesis that MT protects the liver from carcinogenesis by relieving oxidative stress, MT knockout (MTKO) mice were injected with Diethylnitrosamine (DEN), a potent liver carcinogen. When compared to wild-type DEN treated mice, the MTKO groups exhibited significantly higher (5-fold) incidence and an accelerated rate of hepatocarcinogenesis. Gene expression analysis at the preneoplastic stage revealed a dramatic increase in the levels of Serpine-1 in the MTKO mice, which was validated by real-time PCR. Serpine-1, a tissue glycoprotein and an active suppressor of fibrinolysis through the inhibition of tissue plasminogen activator and urokinase plasminogen activator, is also believed to increase cell migration and angiogenesis. Real-time PCR analysis of the pro-inflammatory cytokines known to induce Serpine-1 revealed substantial upregulation of TNF-α, IL-6, and IL-1β in the MTKO/DEN mice compared to the WT/DEN and untreated controls. Electrophoretic mobility shift assay confirmed differential activation of NF-κB, a downstream effector of pro-inflammatory cytokines and inducer of Serpine-1 expression, in the MTKO/DEN mice at the preneoplastic stage. These data demonstrate that Serpine-1 and NF- κB act in concert at the early stages of hepatocarcinogenesis when free radical scavenging is compromised. These data show the protective role of MT against HCC induction in a mouse model and provide the rationale for an alternate therapeutic strategy in HCC therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 909. doi:10.1158/1538-7445.AM2011-909

Time-course expression of metallothioneins and tissue metals in chronic relapsing form of experimental autoimmune encephalomyelitis.

To elucidate the role of metallothioneins (MTs) in the pathomechanisms of autoimmune CNS disorders we estimated the expression of MTs I+II and the tissue concentrations of Zn²+ and Cu²+ in the brain, spinal cord (SC) and in the liver during the periods of attacks and remissions in chronic relapsing experimental autoimmune encephalomyelitis (CR-EAE). Disease was induced in the genetically susceptible Dark Agouti (DA) rats by subcutaneous injection of bovine brain homogenate in CFA. Control rats were treated with CFA. The data, obtained by clinical assessment, immunohistochemistry and inductivity coupled plasma spectrometry, have shown that during the first attack (on the 12th day) MTs I+II were markedly upregulated in subarachnoid regions and perivascular space on astrocytes, microglia and on spinal neurons. Simultaneously, the concentrations of zinc in the SC and zinc and copper in the liver have found to be increased. During the second attack (on the 22nd day) a new overexpression of MTs was found in the cerebellum, in sulcus hippocampi, in spinal neurons and particularly in hepatocytes around the central vein. Concomitantly, in the brain and SC the concentration of copper increased. The data point to a neuroprotective role of MTs and to an important regulatory role of essential metals and hepatic MTs in the pathogenesis of CR-EAE.

Role of Metallothioneins in Adaptation of Lymnaea stagnalis (Mollusca: Pulmonata) to Environment Pollution

The efficiency of the heavy metals (zinc, copper and cadmium) binding by metallothioneins (MT), content of MT (MT-SH) and characteristics of antioxidant protective system were determined in the digestive gland of the pond snail Lymnaea stagnalis from the water bodies of Belarus – relatively clean and two industrially polluted. Elevated content of zinc and protein carbonyls were noted in snails from both polluted water bodies. Negative relation between the zinc-binding ability of MT and intensity of lipid peroxidation was proved.

Expression of metallothionein-I and II in skin ageing and its association with skin proliferation

Metallothioneins (MT) are important antioxidants involved in the ageing process of many tissues and organs. To our knowledge, the role of MT in skin ageing has not been reported. To investigate the expression of MT in ageing skin. The protein levels of MT-I and MT-II in sun-exposed and sun-protected skin specimens obtained from healthy individuals were detected by immunohistochemistry using tissue microarray and expressed as average integrated optical density (AIOD). Proliferating cell nuclear antigen (PCNA) and Ki-67 protein levels in these specimens were also detected to study the possible link between the proliferation of keratinocytes and expression of MT. The protein levels of MT-I and MT-II decreased significantly with increasing age of sun-exposed and sun-protected skin (r = -0·73 and -0·98, respectively, P < 0·01) but was more prominent in sun-exposed skin. In sex- and age-matched specimens, the intensity of MT-I and MT-II in sun-exposed skin was much lower than in sun-protected skin (9·46 ± 2·39 vs. 22·25 ± 8·04, mean ± SD of AIOD, P < 0·01, Student's t-test). The expression of PCNA and Ki-67 showed the same trend. The expression of MT-I and MT-II declined with the decrease of keratinocyte proliferation in the process of skin ageing, and this decline was more significant in sun-exposed skin. Whether MT-I and MT-II supplementation could inhibit skin ageing, especially photoageing, merits further study.

Metallothionein in human immunomagnetically selected CD34+haematopoietic progenitor cells

Human umbilical CD34(+) immature haematopoietic cells were rapidly and efficiently obtained from light density MNC (mononuclear cells) by MACS (magnetic cell sorting). An ex vivo expanded population of CD34(+) was cultured in serum-free medium supplemented with cytokines FL (flt3 ligand), SCF (stem cell factor) and TPO (thrombopoietin) in order to obtain a sufficient number of CD34(+) cells. CD34(+) cells expanded from cord blood for 7 days were demonstrated to increase in the absolute number of CD34(+) cells by 5.12 ± 2.47-fold (mean ± S.D., n = 3). Flow cytometric analysis demonstrated that the percentage of CD34 antigen expression after expansion of the culture was 97.81 ± 1.07%, whereas it was 69.39 ± 10.37% in none-expanded CD34(+) cells (mean ± S.D., n = 3), thus defining a system that allowed extensive amplification accompanied by no maturation. MTs (metallothioneins), low molecular weight, cysteine-rich metal-binding proteins, exhibit various functions, including metal detoxification and homoeostasis. We here examined the expression pattern of functional members of the MT gene family in immature CD34(+) cells and compared it with more mature CD34(-) cells in order to strengthen the proposed function of MT in differentiation. Cells were cultured in RPMI 1640 medium, with or without different zinc supplements for 24 h. Relative quantitative expression of MT isogenes in the mature CD34(-) cells was higher than in the immature CD34(+) cells. IHC (immunohistochemical staining) revealed an increased MT protein biosynthesis in CD34(-) cells, greater than in CD34(+) cells. Therefore, the role of MT in differentiation of human haematopoietic progenitor cells from human cord blood is reported for the first time.

Metallothioneins Are Required for Formation of Cross-Adaptation Response to Neurobehavioral Toxicity from Lead and Mercury Exposure in Nematodes

Metallothioneins (MTs) are small, cysteine-rich polypeptides, but the role of MTs in inducing the formation of adaptive response is still largely unknown. We investigated the roles of metallothionein genes (mtl-1 and mtl-2) in the formation of cross-adaptation response to neurobehavioral toxicity from metal exposure in Caenorhabditis elegans. Pre-treatment with mild heat-shock at L2-larva stage effectively prevented the formation of the neurobehavioral defects and the activation of severe stress response in metal exposed nematodes at concentrations of 50 and 100 µM, but pre-treatment with mild heat-shock did not prevent the formation of neurobehavioral defects in 200 µM of metal exposed nematodes. During the formation of cross-adaptation response, the induction of mtl-1 and mtl-2 promoter activity and subsequent GFP gene expression were sharply increased in 50 µM or 100 µM of metal exposed Pmtl-1::GFP and Pmtl-2::GFP transgenic adult animals after mild heat-shock treatment compared with those treated with mild heat-shock or metal exposure alone. Moreover, after pre-treatment with mild heat-shock, no noticeable increase of locomotion behaviors could be observed in metal exposed mtl-1 or mtl-2 mutant nematodes compared to those without mild heat-shock pre-treatment. The defects of adaptive response to neurobehavioral toxicity induced by metal exposure formed in mtl-1 and mtl-2 mutants could be completely rescued by the expression of mtl-1 and mtl-2 with the aid of their native promoters. Furthermore, over-expression of MTL-1 and MTL-2 at the L2-larval stage significantly suppressed the toxicity on locomotion behaviors from metal exposure at all examined concentrations. Therefore, the normal formation of cross-adaptation response to neurobehavioral toxicity induced by metal exposure may need the enough accumulation of MTs protein in animal tissues.

Analysis of metallotionein expression and antioxidant enzyme activities in Meretrix meretrix larvae under sublethal cadmium exposure

To investigate the possible role of metallothioneins (MTs) and antioxidant enzymes in cadmium (Cd) tolerance in Meretrix meretrix larvae, a new MT (designated MmMT) gene was identified and cloned from M. meretrix. The full-length cDNA of MmMT consisted of an open reading frame (ORF) of 231 bp encoding a protein of 76 amino acids, with 21 cysteine residues and a conserved structural pattern Cys-x-Cys-x(3)-Cys-Tyr-Gly-x(3)-Cys-x-Cys-x(3)-Cys-x-Cys-Lys at the C-terminus. The deduced amino acid sequence of MmMT showed about 57–84% identity with previously published MT sequences of mussels and oysters. Real-time PCR was used to analyze the expression level of MmMT mRNA at different M. meretrix larval stages under Cd exposure (25 μg L −1). Results showed that Cd could induce the expression of MmMT mRNA in the larvae, and the expression level increased 5.04-fold and 3.99-fold in D-shaped larvae and pediveligers, respectively. Immunolocalization of MmMT in the stressed larvae revealed that MmMT was synthesized in almost all of the soft parts at the trochophore and postlarva stages, whereas it was only synthesized in the velum and epidermis at the D-shaped larva and pediveliger stages. The activities of three antioxidant enzymes, superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), also were measured in larvae at different developmental stages. Increased enzymatic activities were detected mainly in D-shaped larvae and pediveligers under Cd stress, suggesting that these enzymes respond synchronously with MT. Our results indicate that MmMT and antioxidant enzymes played important roles in counteracting Cd stress in M. meretrix larvae.

Zeptomole Electrochemical Detection of Metallothioneins

BackgroundThiol-rich peptides and proteins possess a large number of biological activities and may serve as markers for numerous health problems including cancer. Metallothionein (MT), a small molecular mass protein rich in cysteine, may be considered as one of the promising tumour markers. The aim of this paper was to employ chronopotentiometric stripping analysis (CPSA) for highly sensitive detection of MT.Methodology/Principal FindingsIn this study, we used adsorptive transfer stripping technique coupled with CPSA for detection of cysteine, glutathione oxidized and reduced, phytochelatin, bovine serum albumin, and metallothionein. Under the optimal conditions, we were able to estimate detection limits down to tens of fg per ml. Further, this method was applied to detect metallothioneins in blood serum obtained from patients with breast cancer and in neuroblastoma cells resistant and sensitive to cisplatin in order to show the possible role of metallothioneins in carcinogenesis. It was found that MT level in blood serum was almost twice higher as compared to the level determined in healthy individuals.Conclusions/SignificanceThis paper brings unique results on the application of ultra-sensitive electroanalytical method for metallothionein detection. The detection limit and other analytical parameters are the best among the parameters of other techniques. In spite of the fact that the paper is mainly focused on metallothionein, it is worth mentioning that successful detection of other biologically important molecules is possible by this method. Coupling of this method with simple isolation methods such as antibody-modified paramagnetic particles may be implemented to lab–on-chip instrument.

Role of metallothionein in cadmium traffic and toxicity in kidneys and other mammalian organs

Metallothioneins are cysteine-rich, small metal-binding proteins present in various mammalian tissues. Of the four common metallothioneins, MT-1 and MT-2 (MTs) are expressed in most tissues, MT-3 is predominantly present in brain, whereas MT-4 is restricted to the squamous epithelia. The expression of MT-1 and MT-2 in some organs exhibits sex, age, and strain differences, and inducibility with a variety of stimuli. In adult mammals, MTs have been localized largely in the cell cytoplasm, but also in lysosomes, mitochondria and nuclei. The major physiological functions of MTs include homeostasis of essential metals Zn and Cu, protection against cytotoxicity of Cd and other toxic metals, and scavenging free radicals generated in oxidative stress. The role of MTs in Cd-induced acute and chronic toxicity, particularly in liver and kidneys, is reviewed in more details. In acute toxicity, liver is the primary target, whereas in chronic toxicity, kidneys are major targets of Cd. The intracellular MTs bind Cd ions and form CdMT. In chronic intoxication, Cd stimulates de novo synthesis of MTs; it is assumed that toxicity in the cells starts when loading with Cd ions exceeds the buffering capacity of intracellular MTs. CdMT, released from the Cd-injured organs, or when applied parenterally for experimental purposes, reaches the kidneys via circulation, where it is filtered, endocytosed in the proximal tubule cells, and degraded in lysosomes. Liberated Cd can immediately affect the cell structures and functions. The resulting proteinuria and CdMT in the urine can be used as biomarkers of tubular injury.

ChemInform Abstract: Studies of Metals and Metallothionein in Tissue

This paper is a review of three topics related to bio-trace metals. First, the transfer of metals into tissues of patients with chronic diseases treated with hemodialysis is examined. Such diseases include chronic hepatitis, diabetes, and chronic renal failure. In these diseases, metal contents from fingernails were flexible but non-specific. Toxicity may appear as the amount of heavy metals in tissues of patients with chronic renal failure treated with hemodialysis. For example, cadmium and lead were not excreted from the blood of patients during the hemodialysis treatment, and, therefore, their amounts gradually increased in the blood of patients. The level of zinc increased and was excreted in the urine of diabetic patients and experimental animals. Calcium accumulated in the kidney of streptozotocin (STZ)-induced diabetic rats that were fed low zinc diets; and, as a result, severe renal failure occurred. From these results, complication syndromes of either metal deficiency or excesses may occur in tissues of patients with chronic diseases. Second, the role of metallothionein (MT), an inducible protein, and the properties of MT isoforms have been studied on experimental animals. In the exocrine cells of the pancreas, MT was induced by various stresses such as zinc, STZ, alloxan and 4-aminopyrazolo-(3,4-d) pyrimidine, but the effects of those stresses were not clear in the endocrine cells. Therefore, MT may have a role in the exocrine cells of the pancreas. In addition, we were able to separate completely MT-1 and MT-2 isoforms in cytosol fractions of tissues using a capillary zone electrophoresis system at neutral pH without any detergents. Each role of the MT isoforms in the tissues soon started to become clear. Third, cisplatin, a platinum-containing anti-tumor drug, did not penetrate into the brain tissue under physiological conditions, as there is a blood-brain barrier to cerebral tissues; however, it did penetrate with either short-term hypoxia or in the case of lipopolysaccharide-treated experimental animals. Nitric oxide, prostaglandin, and free radicals are related to the penetration. Older rats had a higher sensitivity to cisplatin than younger rats.

Hypoxia‐inducible factor 1α is critically involved in metallothionein protection against diabetic cardiomyopathy

Previous studies have shown that metallothionein (MT) protects against diabetic cardiomyopathy (DCM) in mice. The current study was undertaken to test the hypothesis that the protective role of MT against DCM is mediated by hypoxia‐inducible factor ‐1 (HIF‐1) pathway leading to an increased angiogenesis and a normalization of glucose metabolism in a MT cardiac specific over‐expression mouse model and a rat embryonic cardiac fibroblast H9c2 cell line. Streptozotocin‐induced diabetes decreased cardiac HK‐II protein level, a HIF target and an important glycolysis enzyme; and cardiac‐specific MT over‐expression relieved this suppression. MT over‐expression increased HK‐II mRNA level nder both non‐diabetic and diabetic conditions. In vitro analysis showed that MT over‐expression increased and normalized the hyperglycemia‐reduced glycolysis. MT over‐expression significantly prevented the diabetes‐induced reduction in angiogenesis. Further studies showed that MT over‐expression increased HIF‐1α mRNA and protein level in diabetic heart and in MT stable over‐expressing H9c2 cells, indicating the transcriptional modulation of HIF‐1α by MT. This study demonstrated that MT increased HIF‐1 transcriptional activity leading to the normalization of glycolysis and angiogenesis in cardiomyocytes under diabetic conditions. Supported by a grant from American Diabetes Association (W.F)