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*,
* Department of Medicine, the University of Louisville, Louisville, Kentucky
Department of 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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