When Andrea Eckhart, Ph.D., associate professor of medicine at Jefferson Medical College of Thomas Jefferson University in Philadelphia, and her co-workers turned up the volume on GRK5, overexpressing a mouse gene that makes the protein, the researchers saw extreme rises in blood pressure even when the animals were resting.
Not only that, they found that high blood pressure segregated with gender. That is, female mice with an overexpressed GRK5-making gene had a lesser spike in blood pressure than males, which Dr. Eckhart says, has intriguing implications.
"This difference suggests it could be a great model for human hypertension, especially for premenopausal women," says Dr. Eckhart, who is director of the Eugene Feiner Laboratory in the Center for Translational Medicine in the Department of Medicine at Jefferson Medical College. "Is the difference due to a protective effect of estrogen, or because males with testosterone make it worse? We're now looking at the effects of these androgens in conferring differences."
Dr. Eckhart thinks it could be a "powerful hypertensive model to look at different new hypertensive therapies that different drug companies come up with to look at the effects of estrogen."
To Dr. Eckhart and her group, which reported their results August 23, 2005 in Circulation, a journal of the American Heart Association, the finding is another step in the laboratory's goal of uncovering the molecular roots of hypertension. More than 90 percent of cases can't be pinned to a particular molecular cause.
GRK5, short for G-coupled protein receptor kinase, was known to rise in animal models with high blood pressure. According to Dr. Eckhart, this kinase acts as a switch that essentially turns off receptors. Such receptors bind catecholamines, which are sympathetic system neurotransmitters like epinephrine and norepineprhine. They also bind peptide hormones such as angiotensin, which is implicated in high blood pressure.
Dr. Eckhart and her co-workers don't think that GRK5 is necessarily the sole cause of hypertension. But because it is correlated with some types, they wanted to look at the molecular mechanisms and try to get a better idea of its role. They created mice that overexpressed GRK5 in the vascular smooth muscle, hoping to "begin seeing what receptors and signaling pathways might be involved in hypertension with elevated GRK5 levels." What they found surprised them.
"There are not too many molecules shown in mice to raise basal blood pressure straight up," she says. "The effect is quite profound. There are a lot of checks and balances that keep the pressure down. We were surprised there was such an increase at resting. We might have thought this would happen if we stressed the animal, but we saw it at baseline. Obviously it is affecting receptors important in the resting state."
When they looked more closely, they found that increases in blood pressure differed according to sex.
"Ultimately, we'd like to see if GRK5 is a biomarker, a predictor for a multifactorial disease like high blood pressure," she says. "Developing a good therapeutic profile for such patients might helps us prescribe the correct drugs more quickly. We hope the work might lead to better, more specific ways to treat high blood pressure than currently used diuretics and specific receptor blockers." She notes that even though these mice have hypertension, their blood vessels are not enlarged, which is typical of progressive heart failure and kidney disease and are associated with high blood pressure. "These mice didn't have these associated cardiovascular risks," she says. "Maybe the GRK5 is somehow protective of other organs, despite its role in causing hypertension.
Dr. Eckhart's group, in collaboration with Bonita Falkner, M.D., professor of medicine at Jefferson Medical College and Kumar Sharma, M.D., director of the Center for Diabetic Kidney Disease at Thomas Jefferson University and professor of medicine at Jefferson Medical College, currently is studying children with hypertension to examine white blood cell levels of GRK5.