New Model Shows Gender Differences In High Blood Pressure, Jefferson Scientists Find

WhenAndrea Eckhart, Ph.D., associate professor of medicine at JeffersonMedical College of Thomas Jefferson University in Philadelphia, and herco-workers turned up the volume on GRK5, overexpressing a mouse genethat makes the protein, the researchers saw extreme rises in bloodpressure even when the animals were resting.

Not only that, theyfound that high blood pressure segregated with gender. That is, femalemice with an overexpressed GRK5-making gene had a lesser spike in bloodpressure than males, which Dr. Eckhart says, has intriguingimplications.

“This difference suggests it could be a great modelfor human hypertension, especially for premenopausal women,” says Dr.Eckhart, who is director of the Eugene Feiner Laboratory in the Centerfor Translational Medicine in the Department of Medicine at JeffersonMedical College. “Is the difference due to a protective effect ofestrogen, or because males with testosterone make it worse? We’re nowlooking at the effects of these androgens in conferring differences.”

Dr.Eckhart thinks it could be a “powerful hypertensive model to look atdifferent new hypertensive therapies that different drug companies comeup with to look at the effects of estrogen.”

To Dr. Eckhart andher group, which reported their results August 23, 2005 in Circulation,a journal of the American Heart Association, the finding is anotherstep in the laboratory’s goal of uncovering the molecular roots ofhypertension. More than 90 percent of cases can’t be pinned to aparticular molecular cause.

GRK5, short for G-coupled proteinreceptor kinase, was known to rise in animal models with high bloodpressure. According to Dr. Eckhart, this kinase acts as a switch thatessentially turns off receptors. Such receptors bind catecholamines,which are sympathetic system neurotransmitters like epinephrine andnorepineprhine. They also bind peptide hormones such as angiotensin,which is implicated in high blood pressure.

Dr. Eckhart and herco-workers don’t think that GRK5 is necessarily the sole cause ofhypertension. But because it is correlated with some types, they wantedto look at the molecular mechanisms and try to get a better idea of itsrole. They created mice that overexpressed GRK5 in the vascular smoothmuscle, hoping to “begin seeing what receptors and signaling pathwaysmight be involved in hypertension with elevated GRK5 levels.” What theyfound surprised them.

“There are not too many molecules shownin mice to raise basal blood pressure straight up,” she says. “Theeffect is quite profound. There are a lot of checks and balances thatkeep the pressure down. We were surprised there was such an increase atresting. We might have thought this would happen if we stressed theanimal, but we saw it at baseline. Obviously it is affecting receptorsimportant 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 amultifactorial disease like high blood pressure,” she says. “Developinga good therapeutic profile for such patients might helps us prescribethe correct drugs more quickly. We hope the work might lead to better,more specific ways to treat high blood pressure than currently useddiuretics and specific receptor blockers.”

She notes that eventhough these mice have hypertension, their blood vessels are notenlarged, which is typical of progressive heart failure and kidneydisease and are associated with high blood pressure. “These mice didn’thave these associated cardiovascular risks,” she says. “Maybe the GRK5is somehow protective of other organs, despite its role in causinghypertension.

Dr. Eckhart’s group, in collaboration with BonitaFalkner, M.D., professor of medicine at Jefferson Medical College andKumar Sharma, M.D., director of the Center for Diabetic Kidney Diseaseat Thomas Jefferson University and professor of medicine at JeffersonMedical College, currently is studying children with hypertension toexamine white blood cell levels of GRK5.