When Andrea Eckhart, 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.

They found also that high blood pressure segregated with gender.
Female mice with an overexpressed GRK5-making gene had a lesser spike in blood pressure than males.

“ This difference suggests it could be a great model for human hypertension, especially for premenopausal women,” says Eckhart. “ 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.”

To Eckhart and her group, which reported their results 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.

GRK5, short for G-coupled protein receptor kinase, was known to rise in animal models with high blood pressure.
According to 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.

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.”

“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.

Source: Thomas Jefferson University, 2005


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