Cytochrome P450 Lowers Blood Pressure in Transgenic Mouse Model

Mice that were genetically engineered to express human cytochrome P450 (CYP) epoxygenases in their endothelial cells were protected from the effects of diet and drug treatment designed to induce high blood pressure.

The action of CYP epoxygenases on 20-carbon essential fatty acids, such as arachidonic acid, produces epoxyeicosatrienoic acids or EETs. These nonclassic eicosanoids act as short-range hormones of the cardiovascular system and kidney. They produce vasorelaxation as well as anti-inflammatory and profibrinolytic effects. EETs are metabolized by the soluble epoxide hydrolase to the corresponding vicinal diol, or dihydroxyeicosatrienoic acids (DHETs), which are biologically less active.

Investigators at the [U.S.] National Institute of Environmental Health Sciences (Research Triangle Park, NC, USA) in collaboration with colleagues at the University of North Carolina (Chapel Hill, USA) genetically engineered a strain of mice with endothelial expression of the human CYP2J2 and CYP2C8 epoxygenases to increase endothelial EET biosynthesis.

They reported in the May 21, 2010, online edition of the FASEB Journal that when transgenic and control mice were fed a high-salt diet and received subcutaneous angiotensin II administered over a four week period, the angiotensin/high-salt-induced an increase in systolic blood pressure, proteinuria, and glomerular injury. These effects were significantly attenuated in the CYP2J2 and CYP2C8 transgenic mice compared to wild-type controls.

"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 first author Dr. Craig R. Lee, assistant professor of pharmacy at the University of North Carolina. "We hope that these studies will advance the development of new treatments for high blood pressure.”

Related Links:
[U.S.] National Institute of Environmental Health Sciences
University of North Carolina