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Building Bones in Thalassemia Patients
New Bone Density Study in Patients with Thalassemia Shows Need for Intervention at Younger Ages

In a study recently published in the American Journal of Physiology-Heart and Circulatory Physiology, CHORI scientist Julie Saba, MD, PhD, and her colleagues have identified a new target that has the potential to revolutionize heart attack treatment and help prevent heart disease-related deaths – the number one cause of death in the United States. For the first time, the study shows that the enzyme, sphingosine 1-phosphate lyase (SPL), may be a novel target for reducing heart-attack-induced heart injury, or ischemia-reperfusion injury (I/R).

"We were able to show for the first time that SPL is activated as a result of ischemia. This raised the possibility that preemptively inhibiting the SPL enzyme might reduce the consequences of I/R injury on the heart," says Dr. Saba.

“We were able to show for the first time that SPL is activated as a result of ischemia.”

Ischemia-reperfusion injury is a two-fold situation in which an individual first has a temporay blockage that reduces blood flow through the coronary arteries of the heart. This reduced blood flow causes injury to the heart cells by depriving them of oxygen, growth factors and other essential nutrients. The second part of the injury occurs when the blockage disappears and blood flow is restored.

"You wouldn't think that restoring blood flow would be a bad thing, but in this case, the cells of the heart are already damaged from the temporary blockage of blood flow," explains Dr. Saba. "When they are re-exposed to the oxygen and nutrients they were missing, they don't handle them very well, and the end result is that the cells generate reactive oxygen species -- molecules that can cause DNA damage and further injure the cells."

Dr. Saba has demonstrated in her new study, however, that reducing SPL levels through what she refers to as an SPL blockade, could provide a strategy to limiting the amount of I/R damage that occurs in the heart. SPL is the enzyme responsible for breaking down sphingosine 1-phosphate (S1P), a lipid metabolite found in tissues and in the blood. S1P promotes cell growth and survival, especially under stressful conditions such as those faced by heart cells immediately after a heart attack.

"Previous studies have indicated that S1P appears to be a cardioprotectant," says Dr. Saba. "We wanted to know whether inhibiting SPL would increase S1P levels in the heart and circulation and, importantly, whether this strategy would protect the heart by reducing I/R injury and improving functional heart recovery."

Using a combination of genetic and pharmacological approaches to reduce SPL activity, Dr. Saba and her colleague Dr. Joel Karliner, a cardiologist at the at the San Francisco VA Medical Center, showed that this strategy does prevent tissue injury and improve functional recovery of mouse hearts subjected to I/R. While this information has been applied in other areas of research, such as autoimmune disease and cancer, Dr. Saba's study is the first to assess the impact of reducing SPL activity as part of I/R treatment.

“It would be ideal if we could inhibit SPL and raise S1P levels acutely and temporarily if someone is having a heart attack. There are SPL inhibitors already available that have been approved for other uses, and it would be expedient if we could apply them to this very prevalent problem.”

The most significant results of the study are that in both a genetic mouse model with low SPL levels, and using a small molecule inhibitor in a normal mouse heart, Dr. Saba showed that blocking SPL protected the heart from I/R injury.

"The decreased SPL levels reduced the level of infarct, maintaining more healthy heart tissue and thereby achieving better functional recovery," says Dr. Saba.

In these studies, SPL was inhibited preemptively before ischemia occurred. Future studies will need to establish whether inhibiting SPL after ischemia can prevent heart injury and improve recovery as well.

“It will be very important for us to determine if this can also work after the fact, because of course, people don’t come into the emergency room saying I’m going to have a heart attack tomorrow.”
"We must be able to successfully intervene after the heart has already been impacted. We are working on those studies right now," says Dr. Saba.

In addition, Dr. Saba is exploring whether this strategy will be effective at preventing heart injury from other causes. As a pediatric oncologist, she is especially interested in determining if SPL blockade could prevent the toxic effects of some chemotherapy drugs and radiation used to treat cancer.

"We are learning that certain chemotherapeutic drugs can produce toxic effects on the heart that may not become evident until many years after treatment for a childhood cancer," explains Dr. Saba. "It would be very beneficial to protect the heart at the time of chemotherapy administration and thereby reduce the risks of late effects, so that our children with cancer are not only cured but also as healthy as possible in the long run."


Friday, June 10, 2011 9:54 AM

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