New study in 'Nature' demonstrates protection against cell death during heart attack

03/28/05

CINCINNATI -- A new study, conducted at Cincinnati Children's Hospital Medical Center and published in the journal Nature, has uncovered a fundamental mechanism by which cells die – a finding that could quickly lead to improved emergency treatments for heart attack and stroke.

The Cincinnati Children's researchers discovered that blocking a particular protein in mice protects the heart from injury due to loss of blood flow during a heart attack. Moreover, drugs already exist that block this protein – cyclophilin D – but they have never been used in actual patient care, partially because data didn't exist until now to prove they would work, according to Jeff Molkentin, Ph.D., a researcher at Cincinnati Children's and the study's senior author.

Cyclophilin D resides within the mitochondria of a cell. The mitochondria are the power plants of a cell and are responsible for the majority of energy production. When mitochondria do not function properly, such as when tissue is deprived of oxygen, cells begin to die through a process involving rupture of the mitochondria. When cyclophilin D is deleted from the mitochondria, however, a cell's ability to die is blocked, according to Dr. Molkentin.

"When a person comes to a hospital and it's realized that he or she is having a heart attack or stroke, one of the first things done is to re-establish blood flow," says Dr. Molkentin. "At this point, cells have not yet died. But when flow is re-established there is a huge burst of reactive oxygen, and that's when cells die. We hypothesize that if, at the same time you re-establish flow you infuse a cyclophilin D inhibitor, you might profoundly affect the heart or brain and, presumably, protect it."

A class of drugs already exists that blocks cyclophilin D. The most well known one is cyclosporine, a drug used to prevent rejection in organ transplantation. Cyclosporin has a downside, however. In addition to blocking cyclophilin D, it also blocks calcineurin, an agent that protects the immune system. Fortunately, there are so-called analogs of cyclosporin that block cyclophilin D but do not affect the immune system.

While these drugs have not yet been tested in humans, there have been numerous studies indicating they protect against stroke in many different animal models, according to Dr. Molkentin, a scientist in the division of Molecular Cardiovascular Biology at Cincinnati Children's.

"Our study suggests that these drugs should be re-evaluated for injury related to loss of blood flow," says Dr. Molkentin. "Although our study was in a mouse model and looked at the heart, studies in cell culture indicate similar benefits when blood flow causes injury to the brain, kidney and liver. The data support clinical trials. Cyclosporin already has been tested in humans and has been well-tolerated acutely."

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