The results are a key finding that may help researchers develop a new treatment for patients with heart failure where the loss of cells is primarily due to cell suicide.
In the Journal of Biological Chemistry, published online Jan. 24, VCU researchers found that treatment with Viagra, generically known as sildenafil citrate, at clinically relevant concentrations produced therapeutic levels of nitric oxide (NO) in the heart cells of mice by increasing protein levels of two enzymes responsible for the synthesis of NO.
Employing a cellular model where heart attack-like conditions are simulated in a Petri dish, they demonstrated that NO produced from sildenafil inhibits cell death by stabilizing mitochondria, increasing the level of the anti-death protein, Bcl-2, and inhibiting caspase 3, the protein considered to be the ultimate weapon in cell suicide.
"This research has established a strong basis for the design of future studies targeted toward investigating the clinical effects of sildenafil on survival of heart muscle following a major heart attack," said Rakesh C. Kukreja, Ph.D., professor of medicine, physiology and biochemistry at VCU, and lead author of the study.
"In addition, these findings suggest that this drug may slow or possibly reverse the progressive loss of heart cells during chronic heart failure in patients with coronary artery disease," he said.
Researchers used heart cells prepared from genetically engineered mice that lack nitric oxide synthesizing enzymes. The model was particularly useful in studying the protective effect of sildenafil in heart muscle cells independent of any vascular effects or other types of cells, Kukreja said.
According to Kukreja, sildenafil not only protected against necrosis, accidental cell death occurring due to oxygen deprivation, but also against apoptosis, cell death following DNA fragmentation. Furthermore, the researchers found the presence of phosphodiesterase-5 (PDE-5), an enzyme responsible for the destruction of the cGMP molecule, in the heart cells. The cGMP is an intracellular messenger molecule that plays an important role in the dilation of arteries in the body. Sildenafil is able to preserve cGMP, and therefore dilation of the arteries by inhibiting PDE-5.
"These observations have far-reaching implications for the treatment of patients with heart failure where loss of cells is primarily due to apoptosis," he said.
Kukreja and his colleagues began studying sildenafil in 2002 as part of an on-going research program into "preconditioning," which is a way to protect the heart muscle from serious damage in the future by depriving it for very brief periods of blood flow and, therefore, oxygen. In papers published in the September 2002 issue of the American Journal of Physiology, and the March 2003 issue of Circulation Research, Kukreja and his colleagues observed a powerful, protective effect of sildenafil in the heart during experimental heart attack in animal models.
This research is supported by a grant from the National Institutes of Health.
The study is available by calling University News Services at (804) 828-1231.
About VCU and the VCU Medical Center: Located on two downtown campuses in Richmond, Va., Virginia Commonwealth University is ranked nationally by the Carnegie Foundation as a top research institution and enrolls more than 28,500 students in more than 170 certificate, undergraduate, graduate, professional and doctoral programs in the arts, sciences and humanities in 15 schools and one college. Forty of the university's programs are unique in Virginia, and 20 graduate and professional programs have been ranked by U.S. News & World Report as among the best of their kind. MCV Hospitals, clinics and the health sciences schools of Virginia Commonwealth University compose the VCU Medical Center, one of the leading academic medical centers in the country. For more, see www.vcu.edu.
Journal
Journal of Biological Chemistry