COLUMBUS, Ohio--A study led by Ohio State University cardiovascular researchers uncovered a key mechanism that controls blood vessel health and is likely to play a role in high blood pressure, heart attacks, stroke, and atherosclerosis. They describe a molecular switch that causes the endothelial cells that line blood vessels to either promote vascular dilation or constriction.
The findings may lead to new therapies for high blood pressure, also known as hypertension, or improved vascular health in people at risk for cardiovascular disease. When blood vessels lose the ability to dilate properly, it can lead to hypertension, heart attack, stroke, kidney failure, vision problems, and erectile dysfunction. Hypertension and cardiovascular disease affect 81 million Americans and cause more than 830,000 deaths each year.
The research was published in a recent issue of the journal Nature.
“The exciting thing is that by flipping this molecular switch, we could go from a diseased state to a normal state,” says principal investigator Jay L. Zweier, professor of cardiovascular medicine at Ohio State. “There are not many opportunities in which a molecular trigger causes such a direct effect.”
Zweier and his colleagues discovered a molecular modification that switches the function of a key enzyme in endothelial cells, called endothelial nitric oxide synthase, or eNOS. Under normal conditions, eNOS produces nitric oxide (NO), a gas that acts as a cellular signal and leads to dilation of blood vessels. NO signals also discourage the adhesion of cells along the interior of vessels that leads to atherosclerotic plaques.
But if a cell has a buildup of oxidative stress, the eNOS enzyme switches from making NO to pumping out a molecule called superoxide, an oxygen molecule with an extra electron and a negative charge. Superoxide is a reactive oxygen species that has the opposite effects of NO and causes blood vessel constriction and the sticking of cells that form atherosclerotic plaques.
“Superoxide flips the biology of cell signaling and vascular function and causes the reverse effect,” explains Zweier. Until now, it was unclear how molecular modification of eNOS causes it to switch from producing nitric oxide to making its harmful twin, superoxide, he says.
Working at Ohio State’s Davis Heart and Lung Research Institute, Zweier’s team discovered that during periods of oxidative stress, the eNOS enzyme is modified by the addition of two glutathione molecules. This bulky addition uncouples an enzymatic site critical to NO production and leads instead to superoxide generation. The researchers could reverse the modification, called S-glutathionylation, by adding the chemical reducing agent DTT.
Zweier’s team showed that the same S-glutathionylation modification of eNOS occurs in the endothelial cells that line the blood vessels of animals, and that the change caused vessels to remain constricted instead of relaxed. Adding DTT reversed the effect, causing the vessels to dilate.
Finally, the team showed that vessels from rats with hypertension had much higher levels of S-glutathionylation of eNOS relative to healthy animals. In these vessels relaxation was impaired but it was restored to normal after reversal of this modification.
The oxidative stress that leads to the modification of eNOS can occur in a variety of other conditions, associated with inflammation, such as following a heart attack or stroke, atherosclerosis, diabetes and cancer treatment, Zweier says. In these conditions cells can develop an excess of reactive oxygen molecules such as superoxide and hydrogen peroxide that trigger a vicious cycle that produces even more superoxide.
“A small oxidative stress can trigger a bigger oxidative stress, acting like an amplifier,” says Zweier. “But reducing agents similar to DTT can potentially flip the eNOS switch back and ameliorate cardiovascular diseases.”
His group will focus next on identifying drugs or vitamin-like compounds that might work as effectively as DTT and also be safe for animal and eventually human use. “The next step will be finding the best, most effective and least toxic therapeutic to see if we can reverse or ameliorate hypertension and other cardiovascular disease in animals and patients.”
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