|KANG, Y - U NORTH DAKOTA
|CHEN, YAN - U NORTH DAKOTA
Submitted to: Trace Elements in Man and Animals International Symposium
Publication Type: Proceedings
Publication Acceptance Date: 5/19/1996
Publication Date: N/A
Interpretive Summary: Catalase is a major enzyme involved in detoxification of hydrogen peroxide, a form of highly reactive oxygen that is destructive to tissues. The activity of catalase in the heart is very low, being only about 2% of that of the liver in the mouse. This relative inability to dispose of reactive oxygen species may be responsible for the unusual sensitivity of the heart to oxidative injury. The objective of this research was to determine whether selective elevation of catalase activity in the mouse heart by genetic methods can provide protection against oxidative toxicity to the heart. The gene for elevated catalase in the heart was successfully inserted and bred into mice. Transgenic mice were identified by molecular biological methods and by measuring catalase activities in the heart and other organs. Fifteen mouse lines have been produced in which catalase and no other antioxidant is overexpressed in the atria and ventricles of the heart. Each transgenic line exhibits a stably elevated heart catalase activity ranging for 2- to 500-fold higher than normal. This model was found to be protective against oxidative damage induced by the anti-cancer drug adriamycin. This model will be useful for studying oxidative mechanisms in copper-deficient mice. Such studies will help scientists and consumers understand the trace element nutrition of the cardiovascular system.
Technical Abstract: Our previous studies have shown that copper deficiency selectively induces lipid peroxidation in the heart of rats. Further study revealed that the heart contains weak antioxidant systems compared to other tissues. In particular, catalase activity per g heart tissue is very low, being only about 2% that of the liver. Because catalase is a major enzyme involved in detoxification of hydrogen peroxide (H2O2) in mammalian cells, this relative deficit in ability of the heart to dispose of reactive oxygen species may be responsible for the high sensitivity of the heart to oxidative injury. The objective of this research is to determine whether elevation of catalase activity specifically in the heart of transgenic mice can provide protection against oxidative cardiotoxicity. A transgene for overexpression of catalase in the heart was constructed to contain fragments from the rat catalase cDNA ligated behind the alpha cardiac myosin heavy chain promotor. The transgenic mice were identified by using Southern and Dot blot, and PCR procedures. Only catalase, not other anti- oxidants including superoxide dismutase, glutathione peroxidase, glutathione reductase, glutathione, and metallothionein, is overexpressed in the heart, in other atria and ventricles. Each transgenic line exhibits a stably elevated catalase activity, ranging from 2- to 500-fold higher than normal. This enzyme activity is not altered in any other organs including liver, kidneys, and lungs, and skeletal muscles. This model is ideal to study the role of catalase in protection against copper deficiency induced oxidative injury to the heart. Supported by NIH Grant CA68125 and USDA Grant 9500668.