PRECLINICAL STUDY
Attenuation by Metallothionein of Early Cardiac Cell Death via Suppression of Mitochondrial Oxidative Stress Results in a Prevention of Diabetic Cardiomyopathy
Lu Cai, MD, PhD*, , ,*,
Yuehui Wang, MD, PhD*,
Guihua Zhou, MD, PhD*,
Teresa Chen, PhD,
Ye Song, MD, PhD*,
Xiaokun Li, MD, PhD,* and
Y. James Kang, DVM, PhD*,
* Medicine
Pharmacology and Toxicology, the University of Louisville, Louisville, Kentucky
School of Pharmaceutical Sciences, Wenzhou Medical College, Wenzhou, China
Manuscript received April 7, 2006;
revised manuscript received June 15, 2006,
accepted June 19, 2006.
* Reprint requests and correspondence: Dr. Lu Cai or Dr. Xiaokun Li, 511 South Floyd Street, MDR 533, Louisville, Kentucky 40202. (Email: L0cai001{at}louisville.edu).
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.
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Abbreviations and Acronyms
| | ANOVA = analysis of variance | | Gpx = glutathione peroxidase | | GR = glutathione reductase | | GSH = glutathione | | GSSG = oxidized glutathione | | IGF-1 = insulin-like growth factor 1 | | LVEDP = left ventricular end-diastolic pressure | | MT = metallothionein | | MT-TG = cardiac-specific, metallothionein-overexpressing transgenic | | RNS = reactive nitrogen species | | ROS = reactive oxygen species | | STZ = streptozotocin | | TBARS = thiobarbituric acid-reactive substance | | 3-NT = 3-nitrotyrosine | | TUNEL = terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling | | WT = wild-type |
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