Submitted to: American Journal of Physiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/5/1998
Publication Date: N/A
Interpretive Summary: Metallothionein is a protein that exists in low concentrations in all tissues. It acts as a detoxifying agent and, under such conditions as heavy metal poisoning and other stressors, metallothionein concentration is increased. Some of the stressors against which metallothionein protects suggest that it acts as an antioxidant, that is, by destroying or scavenging highly reactive chemical by-products of oxygen metabolism. Heart attacks produce highly reactive oxygen by-products which are, in part, responsible for the resultant damage to the heart. The object of the present study was to determine whether metallothionein could protect the heart against the oxidative damage of a simulated heart attack. High concentrations of metallothionein were produced in hearts of mice by two methods: by inducing its production with the heavy metal cadmium or by using genetic methods to cause the gene that directs production of metallothionein to be increased in the heart. Hearts of these mice were isolated and subjected to ischemia-reperfusion, that is, stopping nutrient flow to the heart and then restarting it. Hearts from both cadmium-treated and genetically altered mice suffered less damage than did their respective controls in response to ischemia-reperfusion. This indicates that high amounts of metallothionein can protect against the oxidative damage of a heart attack. This knowledge may be beneficial in treating this condition.
Technical Abstract: Oxidative stress is believed to play a major role in ischemia reperfusion injury to the heart. Metallothionein (MT), a potential free radical scavenger, may function in protection against cardiac ischemia reperfusion damage. To test this hypothesis, cardiac MT was increased about 2-fold higher than normal by treating FVB mice with cadmium. The hearts isolated from these animals and the saline-treated controls were subjected to a 50 min of warm (37 deg C) zero-flow ischemia followed by 60 min reflow. Compared with the saline-treated controls, the cadmium-treated hearts showed significantly improved recovery of contractile force (69.2+/-6.0% at the end of 60 min reperfusion, P<0.01). Efflux of creatine kinase from cadmium-treated hearts was reduced by more than 50% (P<0.01). These results were further confirmed by using a transgenic mouse model in which cardiac MT was specifically overexpressed in the heart about 10-fold higher than normal. In addition, the zone of ischemia-reperfusion (50 min ischemia followed by 90 min reperfusion) induced infarction was significantly suppressed by about 40% (P<0.01) in the transgenic heart. The results strongly indicate that MT provides protection against ischemia-reperfusion induced heart injury.