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Metallothionein Suppresses Angiotensin II–Induced Nicotinamide Adenine Dinucleotide Phosphate Oxidase Activation, Nitrosative Stress, Apoptosis, and Pathological Remodeling in the Diabetic Heart

Guihua Zhou, MD, PhD^_*,¶, Xiaokun Li, MD, PhD^¶, David W. Hein, PhD, Xilin Xiang, MD, PhD^_*, James P. Marshall, BS^_*, Sumanth D. Prabhu, MD^_*,,||,_* and Lu Cai, MD, PhD^_*,,,¶,_*

^_* Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky
Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky
Department of Physiology and Biophysics, University of Louisville School of Medicine, Louisville, Kentucky
Department of Radiation Oncology, University of Louisville School of Medicine, Louisville, Kentucky
^|| Medical Service, Louisville Veterans Affairs Medical Center, Louisville, Kentucky
^¶ Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical College, Wenzhou, China.

Manuscript received January 14, 2008; revised manuscript received April 30, 2008, accepted May 5, 2008.

^_* Reprint requests and correspondence: Dr. Lu Cai, 511 South Floyd Street, MDR 533, Louisville, Kentucky 40202. or Dr. Sumanth D. Prabhu (Email: sprabhu{at}louisville.edu).

Objectives: We evaluated metallothionein (MT)-mediated cardioprotection from angiotensin II (Ang II)–induced pathologic remodeling with and without underlying diabetes.

Background: Cardiac-specific metallothionein-overexpressing transgenic (MT-TG) mice are resistant to diabetic cardiomyopathy largely because of the antiapoptotic and antioxidant effects of MT.

Methods: The acute and chronic cardiac effects of Ang II were examined in MT-TG and wild-type (WT) mice, and the signaling pathways of Ang II–induced cardiac cell death were examined in neonatal mouse cardiomyocytes.

Results: Acute Ang II administration to WT mice or neonatal cardiomyocytes increased cardiac apoptosis, nitrosative damage, and membrane translocation of the nicotinamide adenine dinucleotide phosphate oxidase (NOX) isoform p47^phox. These effects were abrogated in MT-TG mice, MT-TG cardiomyocytes, and WT cardiomyocytes pre-incubated with peroxynitrite or superoxide scavengers and NOX inhibitors, suggesting a critical role for NOX activation in Ang II–mediated apoptosis. Prolonged administration of subpressor doses of Ang II (0.5 mg/kg every other day for 2 weeks) also induced apoptosis and nitrosative damage in both diabetic and nondiabetic WT hearts, but not in diabetic and nondiabetic MT-TG hearts. Long-term follow-up (1 to 6 months) of both WT and MT-TG mice after discontinuing Ang II administration revealed progressive myocardial fibrosis, hypertrophy, and dysfunction in WT mice but not in MT-TG mice.

Conclusions: Metallothionein suppresses Ang II–induced NOX-dependent nitrosative damage and cell death in both nondiabetic and diabetic hearts early in the time course of injury and prevents the late development of Ang II–induced cardiomyopathy.

Key Words: metallothionein • diabetic cardiomyopathy • angiotensin II • cardiomyocyte apoptosis • NADPH oxidase • nitrosative damage

Abbreviations and Acronyms   Ang II = angiotensin II   ANOVA = analysis of variance   CAT-TG = catalase-overexpressing transgenic   CTGF = connective tissue growth factor   ET = endothelin   LV = left ventricle/ventricular   MT = metallothionein   MT-TG = cardiac-specific, metallothionein-overexpressing transgenic   NOX = nicotinamide adenine dinucleotide phosphate oxidase   NT = nitrotyrosine   PAI = plasminogen activator inhibitor   RNS = reactive nitrogen species   ROS = reactive oxygen species   STZ = streptozotocin   TNF = tumor necrosis factor   TUNEL = terminal transferase dUTP nick end labeling   WT = wild type

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