Coronary heart disease and stroke - the most common cardiovascular diseases associated with smoking - are the first and third leading causes of death in the United States. The U.S Department of Health estimated that as many as 600,000 people suffered strokes in 2004, with smokers being in the highest-risk category. Various substances in tobacco smoke diminish red blood cells' ability to carry oxygen, encouraging the onset of atherosclerosis, the gradual hardening of the arteries caused by deposits of plaque. These deposits progressively scar and thicken the artery wall and, if clots form, blood flow becomes obstructed. The resulting state of hypoxia - or the absence of oxygen - deprives cells of their critical energy source, leading to extensive cell damage and death.

Nowhere is this more dangerous than in the brain. Brain cells, the body's biggest consumer of energy, rely on aerobic (oxygen-based) respiration as a means of producing the necessary fuel to maintain critical cell functions. However, if the brain's oxygen supply were to suddenly be cut off, as is the case with a stroke, brain cells immediately begin to compensate by consuming whatever small amounts of glucose (their other main form of energy) that are available. But the supply runs out quickly. Such a precipitous drop in oxygen levels rapidly leads to the cell damage and/or apoptosis (cell death) which is commonly the result of a heart attack or stroke.

For Dr. Christof Grewer, a University of Miami researcher and 2004 New Investigator grantee, insight into the effects of hypoxia on brain cells is found at the molecular level, specifically in a single protein called GABA (gamma-amino-butyric acid). GABA's role within cells throughout the body is inhibitory, meaning it counter-balances a stimulus. When a muscle cell reacts to a nerve impulse by twitching, GABA is then produced to inhibit further responses once the stimulus has passed. However, when brain cells are deprived of oxygen, "the cell's excitation and inhibition responses are not functioning," Dr. Grewer explains, "and the release of GABA, which is usually produced in small quantities, becomes unstable and is produced in much larger amounts."

The protein that acts as a GABA transporter, GAT-1, is responsible for determining the amounts released into a cell. However, during a stroke, this process becomes unstable and inaccurate, triggering uncontrolled GABA production.

"An often overlooked side-effect of increased GABA production is the swelling that occurs in both affected and surrounding cells" Dr. Grewer said. "Over-production of GABA plays a major role in offsetting the balance of intra-cell volume, which further constricts blood vessels," effectively setting the stage for another stroke.

"By trying to better understand how GAT-1 influences GABA production, we can begin to look for clinically relevant drug therapies to inhibit it. Eliminating cell inflammation after a stroke would not only reduce the risk of having another, but would lessen side effects by containing the damage to a specific area, preventing a greater number of surrounding cells from being harmed," Grewer explained.