metallothionein and Diabetic-Angiopathies

Cardiac failure is a leading cause for the mortality of diabetic patients, in part due to a specific cardiomyopathy, referred to as diabetic cardiomyopathy, which occurs with or without co-existence of vascular diseases. Although several mechanisms responsible for diabetic cardiomyopathy have been proposed, oxidative stress is widely considered as one of the major causes for the pathogenesis of the disease. Thus, a few laboratories are trying to develop antioxidants used to prevent diabetic cardiomyopathy. Metallothioneins (MTs) are cysteine-rich metal-binding proteins with several biological roles including antioxidant property. We and others have indicated the significant cardiac protection of MT against diabetes using cardiac-specific MT-overexpressing transgenic mice and OVE26MT mice (cross-bred of cardiac MT transgenic mice with genetically engineered diabetic OVE26 mice). Several possible mechanisms responsible for MT's cardiac protection from diabetes were revealed. These include MT's important roles in calcium regulation, zinc homeostasis, insulin sensitization, and antioxidant action. Since MT is ubiquitously expressed in mammalian tissues and is highly inducible by a variety of reagents such as zinc, the clinical potential for inducing cardiac MT as an antioxidant by zinc supplementation to prevent various diabetic complications, including cardiomyopathy, has been explored in diabetic animal models and patients. Since zinc has been therapeutically used for several other non-diabetic diseases in clinics, it provides further potential use of zinc for diabetic patients. Therefore, this review will briefly introduce the biochemical features of MT along with its critical roles in redox homeostasis and antioxidant function in the heart, and then discuss the current research on the prevention of diabetic cardiomyopathy by MT with an emphasis on experimental evidence, possible mechanisms, and clinical implications.

Topics: Amino Acid Sequence; Animals; Cardiomyopathies; Diabetic Angiopathies; Humans; Metallothionein; Mice; Mice, Transgenic; Molecular Sequence Data; Oxidative Stress; Zinc

Diabetic cardiomyopathy has become a major contributor to the increased mortality of diabetic patients. Although the development and progression of diabetic cardiomyopathy are considered to be associated with diabetes-derived oxidative stress, the precise mechanisms for and effectively preventive approaches to diabetic cardiomyopathy remain to be explored. Recent studies showed that reactive oxygen or nitrogen species (ROS/RNS) not only play a critical role in the initiation of diabetic cardiomyopathy, but also play an important role in physiological signaling. Therefore, this review will first discuss the dual roles of ROS/RNS in the physiological signaling and pathogenic remodeling leading to cardiomyopathy under diabetic conditions. The significant prevention of diabetic cardiomyopathy by metallothionein (MT) as a potent and nonspecific antioxidant will be also summarized. It is clearly revealed that although dual roles of peroxynitrite-nitrated proteins have been indicated under both physiological and pathogenic conditions, suppression of nitrative damage by MT in the diabetic heart is the major mechanism responsible for its prevention of diabetic cardiomyopathy. Finally the potential for clinical enhancement of the cardiac MT expression to prevent or delay the occurrence of cardiomyopathy in diabetic patients will also be addressed.

Topics: Cardiomyopathies; Diabetes Mellitus; Diabetic Angiopathies; Humans; Metallothionein; Nitrates; Nitrosation; Reactive Nitrogen Species; Reactive Oxygen Species

Glycogen synthase kinase (GSK)-3beta plays an important role in cardiomyopathies. Cardiac-specific metallothionein-overexpressing transgenic (MT-TG) mice were highly resistant to diabetes-induced cardiomyopathy. Therefore, we investigated whether metallothionein cardiac protection against diabetes is mediated by inactivation of GSK-3beta.. Diabetes was induced with streptozotocin in both MT-TG and wild-type mice. Changes of energy metabolism-related molecules, lipid accumulation, inflammation, nitrosative damage, and fibrotic remodeling were examined in the hearts of diabetic mice 2 weeks, 2 months, and 5 months after the onset of diabetes with Western blotting, RT-PCR, and immunohistochemical assays.. Activation (dephosphorylation) of GSK-3beta was evidenced in the hearts of wild-type diabetic mice but not MT-TG diabetic mice. Correspondingly, cardiac glycogen synthase phosphorylation, hexokinase II, PPARalpha, and PGC-1alpha expression, which mediate glucose and lipid metabolisms, were significantly changed along with cardiac lipid accumulation, inflammation (TNF-alpha, plasminogen activator inhibitor 1 [PAI-1], and intracellular adhesion molecule 1 [ICAM-1]), nitrosative damage (3-nitrotyrosin accumulation), and fibrosis in the wild-type diabetic mice. The above pathological changes were completely prevented either by cardiac metallothionein in the MT-TG diabetic mice or by inhibition of GSK-3beta activity in the wild-type diabetic mice with a GSK-3beta-specific inhibitor.. These results suggest that activation of GSK-3beta plays a critical role in diabetes-related changes in cardiac energy metabolism, inflammation, nitrosative damage, and remodeling. Metallothionein inactivation of GSK-3beta plays a critical role in preventing diabetic cardiomyopathy.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Energy Metabolism; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Inflammation; Metallothionein; Mice; Mice, Inbred Strains; Mice, Transgenic; Myocardium; Ventricular Remodeling

Topics: Angiotensin II; Cardiomyopathies; Diabetic Angiopathies; Humans; Metallothionein; NADP; Oxidative Stress

We evaluated metallothionein (MT)-mediated cardioprotection from angiotensin II (Ang II)-induced pathologic remodeling with and without underlying diabetes.. Cardiac-specific metallothionein-overexpressing transgenic (MT-TG) mice are resistant to diabetic cardiomyopathy largely because of the antiapoptotic and antioxidant effects of MT.. 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.. 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.. 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.

Topics: Angiotensin II; Animals; Apoptosis; Cardiomyopathies; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Fibrosis; Hypertrophy; Metallothionein; Mice; Mice, Transgenic; Myocardium; Myocytes, Cardiac; NADP; Oxidative Stress; Ventricular Remodeling

Many diabetic patients suffer from cardiomyopathy, even in the absence of vascular disease. This diabetic cardiomyopathy predisposes patients to heart failure and mortality from myocardial infarction. Evidence from animal models suggests that reactive oxygen species play an important role in the development of diabetic cardiomyopathy. Our laboratory previously developed a transgenic mouse model with targeted overexpression of the antioxidant protein metallothionein (MT) in the heart. In this study we used MT-transgenic mice to test whether an antioxidant protein can reduce cardiomyopathy in the OVE26 transgenic model of diabetes. OVE26 diabetic mice exhibited cardiomyopathy characterized by significantly altered mRNA expression, clear morphological abnormalities, and reduced contractility under ischemic conditions. Diabetic hearts appeared to be under oxidative stress because they had significantly elevated oxidized glutathione (GSSG). Diabetic mice with elevated cardiac MT (called OVE26MT mice) were obtained by crossing OVE26 transgenic mice with MT transgenic mice. Hyperglycemia in OVE26MT mice was indistinguishable from hyperglycemia in OVE26 mice. Despite this, the MT transgene significantly reduced cardiomyopathy in diabetic mice: OVE26MT hearts showed more normal levels of mRNA and GSSG. Typically, OVE26MT hearts were found to be morphologically normal, and elevated MT improved the impaired ischemic contractility seen in diabetic hearts. These results demonstrate that cardiomyocyte-specific expression of an antioxidant protein reduces damage to the diabetic heart.

Topics: Actins; Animals; Antioxidants; Atrial Natriuretic Factor; Base Sequence; Blood Glucose; Blotting, Northern; Cardiomyopathies; Diabetic Angiopathies; Disease Models, Animal; Gene Expression Regulation; Glutathione Disulfide; Insulin; Metallothionein; Mice; Mice, Transgenic; Molecular Sequence Data; Myocardial Contraction; Oligonucleotide Probes; RNA, Messenger; Transcription, Genetic; Triglycerides