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Medical breakthrough for organ transplants and cardiovascular diseases by Flemish researchers

January 07, 2008

Leuven, Belgium - When a blood vessel clogs up, a localized deficiency of oxygen results, causing the surrounding tissue to die. However, working with mice, VIB scientists connected to the Katholieke Universiteit Leuven have been able to prevent muscular tissue with severe hypoxia from dying. The muscles seem to 'adapt' to the lack of oxygen - a metabolic tour de force that animals also use when hibernating, but that has remained a mystery until now. For the medical world, this discovery signifies an important step forward in limiting damage after a heart attack, for example, or for better preservation of organs awaiting transplants.

No life without oxygen - but oxygen can also be harmful

Oxygen is necessary to life. Humans and animals use oxygen to convert fats and sugars into the energy that keeps all life processes running and maintains the body's temperature. At the same time, oxygen can also be harmful when it is converted into toxic oxygen particles that cause serious damage to tissues and organs.

What about a little less?

Some animals can survive in places with little oxygen. Birds at high altitudes, for example, or animals that live underground or that can dive under water for a long time. Hibernating animals turn their bodily processes down low and live with a reduced amount of oxygen.

We can detect changes in the amount of oxygen with certain sensors. These oxygen meters are essential in adapting the body's metabolism during the changeover from an oxygen-rich to an oxygen-deficient environment.

Oxygen meter PHD1 plays crucial role

Julián Aragonés, Martin Schneider, Katie Van Geyte and Peter Fraisl - under the direction of Peter Carmeliet - have studied the role of the PHD1 oxygen meter. To do this, they used 'knock-out' mice that were unable to produce PHD1. They found that blocking an artery in these mice - thus obstructing the oxygen supply to the muscle - did not lead to the death of the surrounding muscular tissue. This was a very surprising result, since the muscle received too little oxygen to survive under normal circumstances. In the mice lacking the PHD1 oxygen meter, the tissue apparently 'reprogrammed' itself by means of a metabolic shift, so that the muscle needed less oxygen in order to continue to function. Furthermore, less oxygen in the muscle meant fewer toxic oxygen particles and thus less damage. So, the muscle could use the little oxygen that was available in a better and safer manner. These alterations enabled the muscle to stay perfectly healthy in these normally life-threatening conditions. In addition, the researchers also demonstrated that treating healthy mice even briefly with a PHD1-blocker could protect the muscles against oxygen deficiency - which opens a path to new therapies.

New therapeutic possibilities?

These findings have significant implications for several medical applications. Scientists can now begin to investigate whether PHD1-blockers can prevent the damage caused by blockage of a blood vessel through thrombosis or after a heart attack (in which the cardiac muscle experiences a shortage of oxygen). New treatment alternatives may also be possible for strokes, and surgeons may also be able to reduce the oxygen supply to organs for a longer period of time during many types of operations.

The absence of PHD1 might also explain the mysterious adaptations of hibernating animals, with important implications for the preservation of organs for transplant. Such tissues often have to contend with prolonged oxygen deficiency, which destroys their viability for transplantation. If these organs could be kept in a 'hibernation' condition, perhaps more lives could be saved.

VIB (the Flanders Institute for Biotechnology)