Skip to main content
ARS Home » Plains Area » Grand Forks, North Dakota » Grand Forks Human Nutrition Research Center » Healthy Body Weight Research » Research » Publications at this Location » Publication #181348
Title: ALCOHOL-INDUCED MYOCARDIAL FIBROSIS IN METALLOTHIONEIN-NULL MICE: PREVENTION BY ZINC SUPPLEMENTATION

Author
item WANG, LIPENG - UNIV OF LOUISVILLE, KY
item ZHOU, ZHANXIANG - UNIV OF LOUISVILLE, KY
item Saari, Jack
item KANG, Y - UNIV OF LOUISVILLE, KY

Submitted to: American Journal of Pathology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/9/2005
Publication Date: 8/1/2005
Citation: Wang, L., Zhou, Z., Saari, J.T., Kang, Y.J. 2005. Alcohol-induced myocardial fibrosis in metallothionein-null mice: Prevention by zinc supplementation. American Journal of Pathology. 167(2):337-344.

Interpretive Summary: Fibrosis, or excessive deposition of collagen (connective tissue), occurs in hearts of humans who consume too much alcohol. It is an apparent attempt to remodel the damaged heart. The inability to produce fibrosis in animal models of alcoholic cardiomyopathy makes it difficult to study the mechanism of this defect. The present study examined the effect of excessive alcohol on hearts of genetically altered mice (MT-KO)incapable of producing a protective molecule called metallothionein. Hearts of these mice exhibited fibrosis and thus represent a tool for examination of this pathology in animals. Further study showed that dietary supplementation with the micronutrient zinc (Zn) could prevent the occurrence of fibrosis in MT-KO mice. Thus, this study has introduced an animal model by which to examine the pathology of fibrosis in alcoholic hearts and, further, has used this model to show that Zn may play a role in amelioration of this defect.

Technical Abstract: Alcohol-induced cardiomyopathy including fibrosis has been recognized clinically for a long time. However, the pathogenesis of alcoholic cardiomyopathy is incompletely understood. Studies using experimental animals have not fully duplicated the pathological changes in humans. In particular, animal models of alcoholic cardiac fibrosis are not available. In the present study, we have developed a mouse model in which cardiac hypertrophy and fibrosis were produced in metallothionein-knockout (MT-KO) mice fed an alcohol-containing liquid diet for 2 months. The same alcohol feeding did not produce cardiac fibrosis in the wild-type (WT) control mice, although there was no difference in the alcohol-induced heart hypertrophy between the WT control and the MT-KO mice. Supplementation with zinc resulted in prevention of cardiac fibrosis but did not affect heart hypertrophy in the alcohol-fed MT-KO mice, suggesting a specific link between the disturbance in zinc homeostasis and cardiac fibrosis. Serum creatine phosphokinase (CPK) activity was significantly higher in the alcohol-administrated MT-KO mice than in the WT mice, and zinc supplementation decreased serum CPK activities and eliminated the difference between the MT-KO and the WT mice. The present study thus demonstrates that disturbance in zinc homeostasis due to the lack of MT is associated with alcohol-induced cardiac fibrosis and more severe cardiac injury and this unique MT-KO mouse model of alcohol-induced cardiac fibrosis provides a useful tool to investigate specific factors involved in the alcoholic cardiomyopathy.