Cyclophilin D Inhibitors May Protect Heart Cells

Researchers have identified a protein linked to the death of heart cells that occurs when oxygen flow is re-established to areas in the heart that have experienced oxygen deficiency during a heart attack.

"When a person comes to a hospital and it is realized that he or she is having a heart attack or stroke, one of the first things done is to re-establish blood flow,” explained senior author Dr. Jeffery Molkentin, an associate professor in the division of molecular cardiovascular biology at Cincinnati Children's Hospital Medical Center (Ohio, USA). "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.”

Cyclophilin D is a prolyl isomerase located within the mitochondrial matrix and is produced by the Ppif gene. The investigators genetically engineered two lines of mice, one line lacking Ppif and another of mice overexpressing cyclophilin D in the heart.

Results published in the March 31, 2005, issue of Nature revealed that mice lacking Ppif were protected from reactive oxygen burst-induced cell death, whereas cyclophilin D-overexpressing mice showed mitochondrial swelling and spontaneous cell death. Mitochondria isolated from the livers, hearts, and brains of mice lacking Ppif were resistant to mitochondrial swelling and permeability transition, and primary hepatocytes and fibroblasts isolated from these animals were largely protected from calcium ion-overload and oxidative stress-induced cell death.

Drugs such as cyclosporine that block cyclophilin D activity are already available but have not yet been tested in humans for this purpose. "Our study suggests that these drugs should be re-evaluated for injury related to loss of blood flow,” said 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.”




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