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Attenuation by metallothionein of early cardiac cell death via suppression of mitochondrial oxidative stress results in a prevention of diabetic cardiomyopathy.
J Am Coll Cardiol. 2006 Oct 17; 48(8):1688-97.JACC

Abstract

OBJECTIVES

We aimed to test whether attenuation of early-phase cardiac cell death can prevent diabetic cardiomyopathy.

BACKGROUND

Our previous study showed that cardiac apoptosis as a major early cellular response to diabetes is induced by hyperglycemia-derived oxidative stress that activates a mitochondrial cytochrome c-mediated caspase-3 activation pathway. Metallothionein (MT) as a potent antioxidant prevents the development of diabetic cardiomyopathy.

METHODS

Diabetes was induced by a single dose of streptozotocin (STZ) (150 mg/kg) in cardiac-specific, metallothionein-overexpressing transgenic (MT-TG) mice and wild-type (WT) controls. On days 7, 14, and 21 after STZ treatment, cardiac apoptosis was examined by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay and caspase-3 activation. Cardiomyopathy was evaluated by cardiac ultrastructure and fibrosis in the diabetic mice 6 months after STZ treatment.

RESULTS

A significant reduction in diabetes-induced increases in TUNEL-positive cells, caspase-3 activation, and cytochrome c release from mitochondria was observed in the MT-TG mice as compared to WT mice. Cardiac protein nitration (3-nitrotyrosine [3-NT]) and lipid peroxidation were significantly increased, and there was an increase in mitochondrial oxidized glutathione and a decrease in mitochondrial reduced glutathione in the WT, but not in the MT-TG, diabetic mice. Double staining for cardiomyocytes with alpha sarcomeric actin and caspase-3 or 3-NT confirmed the cardiomyocyte-specific effects. A significant prevention of diabetic cardiomyopathy and enhanced animal survival were observed in the MT-TG diabetic mice as compared to WT diabetic mice.

CONCLUSIONS

These results suggest that attenuation of early-phase cardiac cell death by MT results in a significant prevention of the development of diabetic cardiomyopathy. This process is mediated by MT suppression of mitochondrial oxidative stress.

Authors+Show Affiliations

Department of Medicine, the University of Louisville, Louisville, Kentucky, USA. L0cai001@louisville.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17045908

Citation

Cai, Lu, et al. "Attenuation By Metallothionein of Early Cardiac Cell Death Via Suppression of Mitochondrial Oxidative Stress Results in a Prevention of Diabetic Cardiomyopathy." Journal of the American College of Cardiology, vol. 48, no. 8, 2006, pp. 1688-97.
Cai L, Wang Y, Zhou G, et al. Attenuation by metallothionein of early cardiac cell death via suppression of mitochondrial oxidative stress results in a prevention of diabetic cardiomyopathy. J Am Coll Cardiol. 2006;48(8):1688-97.
Cai, L., Wang, Y., Zhou, G., Chen, T., Song, Y., Li, X., & Kang, Y. J. (2006). Attenuation by metallothionein of early cardiac cell death via suppression of mitochondrial oxidative stress results in a prevention of diabetic cardiomyopathy. Journal of the American College of Cardiology, 48(8), 1688-97.
Cai L, et al. Attenuation By Metallothionein of Early Cardiac Cell Death Via Suppression of Mitochondrial Oxidative Stress Results in a Prevention of Diabetic Cardiomyopathy. J Am Coll Cardiol. 2006 Oct 17;48(8):1688-97. PubMed PMID: 17045908.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Attenuation by metallothionein of early cardiac cell death via suppression of mitochondrial oxidative stress results in a prevention of diabetic cardiomyopathy. AU - Cai,Lu, AU - Wang,Yuehui, AU - Zhou,Guihua, AU - Chen,Teresa, AU - Song,Ye, AU - Li,Xiaokun, AU - Kang,Y James, Y1 - 2006/09/27/ PY - 2006/04/07/received PY - 2006/06/15/revised PY - 2006/06/19/accepted PY - 2006/10/19/pubmed PY - 2006/12/9/medline PY - 2006/10/19/entrez SP - 1688 EP - 97 JF - Journal of the American College of Cardiology JO - J Am Coll Cardiol VL - 48 IS - 8 N2 - OBJECTIVES: We aimed to test whether attenuation of early-phase cardiac cell death can prevent diabetic cardiomyopathy. BACKGROUND: Our previous study showed that cardiac apoptosis as a major early cellular response to diabetes is induced by hyperglycemia-derived oxidative stress that activates a mitochondrial cytochrome c-mediated caspase-3 activation pathway. Metallothionein (MT) as a potent antioxidant prevents the development of diabetic cardiomyopathy. METHODS: Diabetes was induced by a single dose of streptozotocin (STZ) (150 mg/kg) in cardiac-specific, metallothionein-overexpressing transgenic (MT-TG) mice and wild-type (WT) controls. On days 7, 14, and 21 after STZ treatment, cardiac apoptosis was examined by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay and caspase-3 activation. Cardiomyopathy was evaluated by cardiac ultrastructure and fibrosis in the diabetic mice 6 months after STZ treatment. RESULTS: A significant reduction in diabetes-induced increases in TUNEL-positive cells, caspase-3 activation, and cytochrome c release from mitochondria was observed in the MT-TG mice as compared to WT mice. Cardiac protein nitration (3-nitrotyrosine [3-NT]) and lipid peroxidation were significantly increased, and there was an increase in mitochondrial oxidized glutathione and a decrease in mitochondrial reduced glutathione in the WT, but not in the MT-TG, diabetic mice. Double staining for cardiomyocytes with alpha sarcomeric actin and caspase-3 or 3-NT confirmed the cardiomyocyte-specific effects. A significant prevention of diabetic cardiomyopathy and enhanced animal survival were observed in the MT-TG diabetic mice as compared to WT diabetic mice. CONCLUSIONS: These results suggest that attenuation of early-phase cardiac cell death by MT results in a significant prevention of the development of diabetic cardiomyopathy. This process is mediated by MT suppression of mitochondrial oxidative stress. SN - 1558-3597 UR - https://www.unboundmedicine.com/medline/citation/17045908/Attenuation_by_metallothionein_of_early_cardiac_cell_death_via_suppression_of_mitochondrial_oxidative_stress_results_in_a_prevention_of_diabetic_cardiomyopathy_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0735-1097(06)01909-7 DB - PRIME DP - Unbound Medicine ER -