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Discovery May Open Doors for New Blood Pressure Treatments

By Robin Mackar
July 2010

Craig  R. Lee, Pharm.D., Ph.D.
Lee, above, said of his experience in Zeldin's group, "I will always be grateful for the tremendous mentorship of Dr. Zeldin and support from NIEHS." (Photo courtesy of Craig Lee)

Darryl  Zeldin, M.D.
Principal Investigator Darryl Zeldin led the 18-member research team that also included scientists from the NIEHS Laboratory of Structural Biology. (Photo courtesy of Steve McCaw)

NIEHS-funded researchers have found that increasing certain proteins in the blood vessels of mice relaxed the vessels, lowering the animal's blood pressure. Their study, published online in The FASEB Journal, provides new avenues for research that may lead to new treatments for hypertension.

"The paper demonstrates that cytochrome P450 plays an important role in the management of high blood pressure, a disease of enormous public health concern," said Darryl Zeldin, M.D. (http://www.niehs.nih.gov/research/atniehs/labs/lrb/enviro-cardio/index.cfm), acting clinical director of the National Institute of Environmental Health Sciences (NIEHS) and senior author on the paper.

According to the Centers for Disease Control and Prevention, about 1 in 3 adults in the United States has high blood pressure (http://www.nhlbi.nih.gov/health/dci/Diseases/Hbp/HBP_WhatIs.html) Exit NIEHS, which increases the risk for heart disease and stroke, the first and third leading causes of death in the United States.

The study (http://www.fasebj.org/cgi/content/abstract/fj.10-160119v1) Exit NIEHS was conducted by researchers at NIEHS who teamed with investigators at the University of North Carolina at Chapel Hill (UNC), Medical College of Wisconsin, Milwaukee, and Oregon Health and Science University, Portland.

The researchers created animal models that had a human cytochrome P450 (CYP450 or P450) in the cells that line their blood vessels. The mice with the P450 generated more substances called epoxyeicosatrienoic acids or EETs, which are known for their role in protecting the cardiovascular system. EETs relax and dilate the blood vessels and fight inflammation.

"We found that when the animals were exposed to substances known to increase blood pressure, the animals with the P450 had lower blood pressure and less damage to the kidneys compared to normal mice," said Craig R. Lee, Pharm.D., Ph.D. (http://pharmacy.unc.edu/faculty-research/faculty-directory/craiglee) Exit NIEHS, assistant professor at the University of North Carolina at Chapel Hill (UNC-CH) and lead author on the paper. "We hope that these studies will advance the development of new treatments for high blood pressure."

"This is a great example of a basic finding that improves our understanding of a metabolic pathway that can be used to develop improved treatments for those suffering from a common disease like hypertension," said Linda Birnbaum, Ph.D., director of NIEHS and the National Toxicology Program.

"The research collaboration also provides an excellent real life example of how we are mentoring and supporting young investigators at NIEHS for their own research careers," Birnbaum added. Lee was a trainee with Zeldin's Environmental Cardiopulmonary Disease Group in the NIEHS Laboratory of Respiratory Biology (see text box).

Citation: Lee CR, Imig JD, Edin ML, Foley J, DeGraff LM, Bradbury JA, et al. (http://www.fasebj.org/cgi/content/abstract/fj.10-160119v1) Exit NIEHS 2010. Endothelial expression of human cytochrome P450 epoxygenases lowers blood pressure and attenuates hypertension-induced renal injury in mice. FASEB J. Epub ahead of print. doi:10.1096/fj.10-160119.

(Robin Mackar is the news director in the NIEHS Office of Communications and Public Liaison and a regular contributor to the Environmental Factor.)

NIEHS Training Experience Shapes Research

Lee completed his dissertation research at NIEHS in the Laboratory of Respiratory Biology under the mentorship of Zeldin. Lee is now an assistant professor at UNC-CH Eshelman School of Pharmacy and the recent recipient of an NIH grant to continue his work in this area. In 2007, he received a beginning grant-in-aid (http://pharmacy.unc.edu/news/schoolnews/craig-lee-receives-grant-from-american-heart-association) Exit NIEHS from the American Heart Association.

"Development of this mouse model was an integral part of my training at NIEHS," Lee said. "It will enable investigators to better understand the role of the P450-EET pathway in various diseases that are impacted by blood vessel function, and is a key component of the ongoing collaboration between my lab at UNC and NIEHS."



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