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(Circulation. 2006;113:544-554.)
© 2006 American Heart Association, Inc.

Heart Failure

Cardiac Metallothionein Induction Plays the Major Role in the Prevention of Diabetic Cardiomyopathy by Zinc Supplementation

Jianxun Wang, MS^*; Ye Song, MD, PhD^*; Laila Elsherif, PhD; Zhenyuan Song, PhD; Guihua Zhou, MD, PhD; Sumanth D. Prabhu, MD; Jack T. Saari, PhD; Lu Cai, MD, PhD

From the Departments of Medicine (J.W., Y.S., Z.S., G.Z., S.D.P., L.C.), Pharmacology and Toxicology (L.E., L.C.), Physiology and Biophysics (S.D.P.), and Radiation Oncology (L.C.), University of Louisville School of Medicine, Louisville, Ky; and Grand Forks Human Nutrition Research Center, US Department of Agriculture, Grand Forks, ND (J.T.S).

Correspondence to Lu Cai, MD, PhD, Department of Medicine, University of Louisville School of Medicine, 511 S Floyd St, MDR 533, Louisville, KY 40202. E-mail L0cai001{at}louisville.edu

Received January 21, 2005; revision received October 27, 2005; accepted November 28, 2005.

Background— Our previous studies showed that transgenic mice that overexpress cardiac-specific metallothionein (MT) are highly resistant to diabetes-induced cardiomyopathy. Zinc is the major metal that binds to MT under physiological conditions and is a potent inducer of MT. The present study therefore explored whether zinc supplementation can protect against diabetic cardiomyopathy through cardiac MT induction.

Methods and Results— Diabetes was induced in mice (C57BL/6J strain) by a single injection of streptozotocin. Half were supplemented intraperitoneally with zinc sulfate (5 mg/kg) every other day for 3 months. After zinc supplementation, mice were maintained for 3 more months and then examined for cardiomyopathy by functional and morphological analysis. Significant increases in cardiac morphological impairment, fibrosis, and dysfunction were observed in diabetic mice but not in diabetic mice supplemented with zinc. Zinc supplementation also induced a significant increase in cardiac MT expression. The role of MT in cardiac protection by zinc supplementation was examined in cultured cardiac cells that were directly exposed to high levels of glucose (HG) and free fatty acid (FFA) (palmitate), treatment that mimics diabetic conditions. Cell survival rate was significantly decreased for cells exposed to HG/FFA but did not change for cells exposed to HG/FFA and pretreated with zinc or low-dose cadmium, each of which induces significant MT synthesis. When MT expression was silenced with the use of MT small-interfering RNA, the preventive effect of pretreatment with zinc or low-dose cadmium was abolished.

Conclusions— These results suggest that the prevention of diabetic cardiomyopathy by zinc supplementation is predominantly mediated by an increase in cardiac MT.

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