February 28,
2000
UCSD RESEARCHERS LINK ANGIOGENESIS FACTOR WITH MYOCARDIAL ISCHEMIA AND INFARCTION
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.