$11 million in NIH Grants Awarded to Physicians at the University of Rochester to Study Cardiovascular Diseases

June 03, 1999

The National Institutes of Health (NIH) has awarded more than $11 million to two University of Rochester physicians, Bradford Berk, M.D., Ph.D., Paul N. Yu Professor of Cardiology, chief of the Cardiology Unit and director of the Center for Cardiovascular Research, and Charles Francis, M.D., professor of Medicine and chief of Vascular Medicine, to probe the cardiovascular system in the hopes of shedding light on new ways to combat diseases such as hypertension, cancer, hemophilia and heart disease.

Berk, is trying to determine why people with hypertension (high blood pressure) are so much more likely to become victims of heart attacks. He's also investigating how a hormone called Angiotensin II, which helps control blood flow, can cause congestive heart failure and hardening of the arteries. Francis is leading a team to uncover how blood vessels repair themselves and aid in the repair of other tissues. Clotting and blood vessel healing malfunctions are major causes of hemophilia, fibrosis, stroke and heart attack.

Berk's Research

Heart attacks kill 500,000 people in the country each year and hypertension is the major contributing risk factor - twice as influential as cigarette smoking. Although doctors have known of the link between hypertension and heart attack, they are not certain how hypertension predisposes a person to heart attacks.

"We suspect there are certain genes that make someone more likely to have a heart attack if they have high blood pressure," says Berk. "We want to find those genes and possibly disable them."

If Berk is able to find the linking genes, doctors may be able to separate those patients at highest risk and begin treatment far sooner than is practiced today.

About one in six American adults suffer from some form of hypertension, which is diagnosed via elevated blood pressure. However, other abnormalities that commonly occur in patients with hypertension include obesity, glucose intolerance which can lead to diabetes, and low levels of HDL, the "good" cholesterol, all of which result in a predisposition toward cardiovascular disease. In addition, high pressure on the walls of arteries can cause many organs to become susceptible to damage, increasing the risk of stroke, kidney damage, and aneurysms as well as heart attack.

Berk will completely chart genes in hypertensive rats that seem more susceptible to hypertension-related heart attacks in order to determine which genes are associated with increased cardiovascular disease. He then hopes to relate these genes to humans to determine which make a person with high blood pressure more susceptible to heart attacks. He estimates that within 5-10 years he may begin human trials to test if the discovered genes actually affect a patient's risk of heart attack.

Current treatment of hypertension includes diuretics, which are drugs that promote the excretion of salt and water. This reduces the work the heart must do to pump blood through the kidneys and other organs. Beta-blockers are also used to reduce the pressure on vessel walls by slowing the heart rate. ACE inhibitors and angiotensin blockers, recent drugs that repress a series of enzymes and hormones that raise blood pressure by constricting blood vessels (commonly called renin angiotensin system), appear to limit the damage hypertension inflicts on the brain, kidneys, and heart.

"What we're hoping to do is find and treat the cause of hypertension, not just treat the blood pressure number," says Berk. "Even with all our treatments today we still have a significant rise in hypertensive heart and kidney disease. Merely lowering blood pressure may not be adequate."

The NIH invited researchers to apply for the grant. Twenty universities applied and Berk's group at The University of Rochester was among the four that were chosen. The University of Rochester conducts a variety of studies in cardiovascular genetics including the long QT syndrome by Dr. Arthur Moss' group. The four-year study will be conducted in the Center for Cardiovascular Research, part of the new Aab Institute of Biomedical Sciences.

Berk is also studying how a hormone that is critical to proper blood flow causes high blood pressure. The hormone, Angiotensin II, helps control the pressure blood exerts on arteries by constricting them. In the long-term, angiotensin II thickens and stiffens arteries, leading to hypertension, atherosclerosis and congestive heart failure.

Francis' Research

Francis is heading a team investigating different aspects of the vascular system's clotting and self-repair systems. He's investigating proteins in the blood that trigger the growth of new blood vessels in the hopes of enhancing blood flow to damaged tissue and choking off blood flow to tumors. Fibrin and fibrinogen, two blood proteins that are critical for clotting blood properly in cases of injury, bind tightly to another protein called Fibroblast Growth Factor 2 (FGF-2), which helps stimulate the growth of new blood vessels.

When either injury or infection damages a tissue, the clotting proteins fibrin and fibrinogen collect at the site of damage. The FGF-2 bound to those clotting proteins piggybacks its way to the area, prompting new blood vessels to grow and supply the damaged area with blood. In some instances, such as when cancer develops in the body, doctors want to stop the formation of new blood vessels to keep the cancer cells from getting the oxygen they need to grow.

"If we can understand how FGF-2 binds to fibrin and fibrinogen, we might be able to strengthen or weaken the bond," says Francis. "Then, when the clotting agents gather in an area, we could influence how much FGF-2 is taken along with them. That would alter whether or not new blood vessels grow in the area."

Francis is also looking into what part of a blood vessel receives the FGF-2's signal to begin growing a new blood vessel, with the same hope of controlling the growth process.

A member of Francis' team, Patricia Simpson-Haidaris, Ph.D., associate professor of Medicine, is looking for a way to keep blood vessels from over-repairing themselves after injury, a condition known as fibrosis. Fibrinogen contributes to the reconstruction of vessel walls by showing them when and where they need to repair themselves. Sometimes, however, the repair does not stop when it should, resulting in fibrosis.

"The fibrinogen revs up any cell that is involved in repair," explains Simpson-Haidaris. "We need to know how fibrinogen interacts with the cells of the blood vessels to learn how to halt the healing process at the right time, or to induce quicker healing in those patients that need it."

To understand how fibrinogen works, Simpson-Haidaris is studying the way that blood vessels in the lung are damaged and repair themselves after pneumonia. Some vessels may leak blood into the surrounding tissue, while the cells of other vessels may die completely. She hopes to discover how fibrinogen identifies where such damage has taken place and how it is able to induce new cells to grow where needed to repair the blood vessel.

The second researcher of Francis' team, professor of Biochemistry and Biophysics, Phil Fay, Ph.D., is working to understand the function a protein that is missing or defective in people with the most common type of hemophilia: hemophilia A. More than 20,000 people in the country with hemophilia A are prone to excessive bleeding because their blood does efficiently clot in a wound, putting them at risk for severe bleeding from relatively minor injuries. In normal individuals, two proteins work together to help clot a wound and prevent excessive blood loss; the first one, called "Factor VIII" accelerates the other, "Factor IXa," multiplying its effectiveness more than a hundred thousand-fold.

"People with hemophilia A are missing the Factor VIII protein, or it's not working right," says Fay. "They're getting one hundred-thousandth the clotting ability they should. We want to learn exactly how Factor VIII works, how it makes Factor IXa become so effective. Then we may be able to reproduce the effect and help these people's blood clot properly."

Current treatment for those suffering from hemophilia A is an injection of Factor VIII, but this has met with limited success in some cases since the body recognizes the protein as an intruder and neutralizes it before it can do much good. By understanding how Factor VIII works, Fay hopes to create a replacement that may have a better chance of eluding the body's immune system and helping the patient's blood to clot when it should.

Lee Ann Sporn, Ph.D., associate professor of Medicine and of Pathology and Laboratory Medicine, is working with Francis' direction to understand how the cells that line the walls of blood vessels, called endothelial cells, contribute to the blood clotting that can contribute to vascular disease, including heart attack, stroke and atherosclerosis.

Sporn will study how rickettsia, the organism that causes rocky mountain spotted fever, changes the way the genes in endothelial cells are expressed, causing them to signal the blood to clot within the vessels and cause the vessels to become inflamed. By watching how this disease does this, Sporn hopes to learn about how these endothelial cells influence blood clotting and inflammation in healthy people.

"We have to understand what role endothelial cells play in clot formation, so we may be better able to control it" says Sporn. Understanding how endothelial cells contribute to inflammation and clotting may give doctors new approaches to diseases of the heart and blood vessels.

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