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UCSD School of Medicine researchers have, for the first time, linked Hypoxia-inducible factor (HIF) to heart disease and heart attack in human patients.

Their findings, reported in the March 2 New England Journal of Medicine, suggest a defensive molecular mechanism launched by the body to protect against the damaging effects of oxygen deprivation on the heart.

In cell cultures and animal studies, HIF, a gene-stimulating factor which is expressed in response to decreased oxygenation, has been found to activate angiogenesis genes that stimulate blood vessel growth. In the UCSD study, HIF was found in tissue samples from human hearts damaged by ischemia or infarction, but not in normal tissue. The researchers also noted a connection between HIF and vascular endothelial growth factor (VEGF), also present in the diseased tissue samples. HIF triggers VEGF, initiating blood vessel growth to increase oxygenation to blood-deprived tissue.

1B: Immunohistochemistry with anti-HIF Antibodies In this figure, HIF localizes to the nuclei of myocardial cells and nuclei of endothelial cells (in the hearts of patients with early ischemia/infarction).	2B: Immunohistochemistry with anti_VEGF Antibodies In this figure, VEGF localizes to the cytoplasm of endothelial cells likely small blood vessels (in the hearts of patients with later ischemia/infarction)

In this study, HIF was identified in biopsies of ischemic or infarct portions of 37 human hearts of patients undergoing coronary bypass surgery. Biopsies from normal areas of the same heart showed no presence of HIF. Biopsies were performed by Patricia Thistlethwaite, M.D., Ph.D., UCSD School of Medicine assistant professor of surgery in the Division of Cardiothoracic Surgery, and Stuart Jamieson, M.B., F.R.C.S., UCSD School of Medicine Professor of Surgery and chief of the Division of Cardiothoracic Surgery.

"We demonstrated that HIF is turned on in the early phases of myocardial ischemia, and that it in turn stimulates the production of VEGF in the heart," said Dr. Thistlethwaite. "Knowing that HIF and VEGF are very strong angiogenesis genes, we sought to understand their role in myocardial ischemia. Through our findings, it is very clear that during a heart attack or ischemia, HIF and VEGF are active responses attempting to increase a decreasing blood flow."

The biopsies were examined by Paul Wolf, M.D., UCSD School of Medicine clinical professor of pathology and director of the autopsy and hematology laboratory at the Veterans Affairs Medical Center, San Diego. Through the biopsy examination, Dr. Wolf identified the degree of damage, ischemia or normalcy in the heart tissue. Chemical studies to identify the presence of HIF and VEGF were performed by Sang Lee, M.D., a UCSD School of Medicine Department of Surgery resident.

These findings, linking HIF and VEGF to ischemia and heart attack, open the door for potential clinical intervention limiting damage from heart attacks at the molecular level.

"Our next step is to deliver HIF by gene therapy into the heart to improve myocardial function, and limit the damage of a heart attack," Dr. Thistlethwaite said.

Also involved in the study were: Ryan Escudero, B.S. and Reena Deutsch, Ph.D.

The study was funded in part by the Nina Braunwald Career Development Award from the Thoracic Surgery Foundation, and by a grant from the National Institutes of Health.