Saturday 25 Oct 2014

Information and opinions presented here do not always represent the views of the American Heart Association.

Mouse study finds a faulty gene may also be at fault for high blood pressure

Published: 3:02 pm CDT, March 17, 2014

All the mice kept dying. Fatal heart defects were wiping out litters of them in a laboratory, frustrating scientists trying to get to the bottom of a gene mystery.

But when researchers in Oklahoma finally figured it out, they stumbled on something big: a possible new contributor to high blood pressure – and maybe the means to treat it.

It comes down to a gene that, when faulty, results in high blood pressure. The finding offers a potential new target for designing a drug to mimic the gene’s beneficial effect.

The gene, called LKB1, switches on an enzyme called AMPK that regulates glucose, fat and cholesterol metabolism to maintain a constant level of energy in the body. Scientists already knew LKB1 thwarts cancer development, but no one had yet explored the gene’s impact on the endothelium, the thin layer of cells that line the inside of blood vessels.

The new study, funded by the American Heart Association and appearing Monday in the journal Circulation, found that mice genetically engineered to lack the LKB1 gene in endothelial cells developed high blood pressure.

“Before this study, there was no research to indicate that this tumor suppressor gene had any effect on blood pressure,” said the study’s lead researcher Ming-Hui Zou, MD, PhD, a professor and vice chair for research in the department of medicine at the University of Oklahoma Health Sciences Center.

Previous attempts to delete the LKB1 gene from endothelial cells proved deadly to mice because the gene makes a protein that helps the heart develop correctly, Zou said. The piece of DNA that researchers had been using to inactivate LKB1 in endothelial cells was having a lethal impact elsewhere in the body.

Zou’s research team made a simple fix: They used a different sequence of DNA that is found mainly in the endothelium. With the effects of LKB1 deletion confined mostly to endothelial cells, some of the mice survived – only to become hypertensive.

Researchers tracked the complex cellular pathway starting from the inactive LKB1 gene, hoping to uncover the chain of events that caused the surviving mice to develop high blood pressure. It led them to AMPK, sitting relatively dormant awaiting instructions from LKB1.No method currently exists to restore the function of an aberrant tumor suppressor gene, Zou said. So the next best thing is to mimic the effect it would normally have: activation of AMPK. “We want to develop a specific pharmacological agent that can activate this protein as a therapy for lowering blood pressure,” said Zou, a recipient of the American Heart Association’s National Established Investigator Award.

AMPK is already the target of metformin, a drug that reduces blood glucose levels and is commonly prescribed to treat Type 2 diabetes. But Zou said his team is looking for a more potent drug than the decades-old metformin.

Drugs commonly used today to treat high blood pressure include diuretics and beta blockers, medications that respectively help the body get rid of excess sodium and water and relieve stress on the heart. But a drug that activates AMPK would work at the cellular level to treat high blood pressure, just like some powerful cancer drugs target a specific protein or pathway responsible for cancer growth.

It will take a few years to identify and test an experimental AMPK-activating drug in mice before testing can begin in people, Zou said. But considering AMPK is less active in other diseases such as obesity, he predicts such a drug could be used to treat a list of conditions.

“Maybe in the future, a single pill could treat high blood pressure, Type 2 diabetes and obesity,” Zou said. “That’s our goal.”