Discovery by the University of Oulu’s research group of a new mechanism that regulates blood pressure
The study focused on a nuclear receptor that senses the chemical environment of cells, the pregnane X receptor (PXR), which is a key regulator in the drug metabolism of the liver.
In a recent article, the researchers show how PXR increases blood pressure in both humans and rats when activated. Regulated by PXR activation, the liver produces 4beta-hydroxycholesterol (4bHC), and its rising concentration is linked to lower blood pressure.
“This is a chain of effects in which 4bHC appears to counteract PXR activation,” says Janne Hukkanen, Professor of Internal Medicine, who was the head researcher.
The study showed that the healthy subjects with the lowest blood pressure had the highest levels of 4bHC. In addition, it was noted that the 4bHC levels in subjects with overweight and obesity were significantly lower than those of normal-weight subjects. This may at least in part explain elevated blood pressure common in people with obesity.
“It is common knowledge that hypertension is more common in people with overweight and obesity than in the normal-weight population, but the underlying mechanism has not been fully established. This finding increases our understanding of elevated blood pressure caused by excess weight and obesity,” Hukkanen says.
Hypertension increases the risk of many cardiovascular events, such as strokes and heart attacks. Therefore, elevated blood pressure is the most important risk factor in reducing healthy life years worldwide.
The discovery of a new blood pressure-regulating circuit may also enable the development of anti-hypertensive drugs that work in a completely new way. “For example, people with overweight and obesity could be offered more effective drugs and better targeted treatment,” Hukkanen says.
PXR has been the subject of active research in recent years. The research group established previously that the activation of PXR causes an increase in harmful LDL cholesterol in humans.
Many drugs, food ingredients and environmental chemicals activate the PXR receptor. Chemicals activating the receptor are also found in many pesticides, flame retardants, plastic additives and environmental pollutants.
“Our research provides strong evidence that the chemical composition of our environment may also play a role in elevated blood pressure,” Hukkanen adds.
The study was conducted collaboratively by the internal medicine and pharmacology researchers of the University of Oulu, Admescope Ltd and the University of Eastern Finland.
The study was funded by the Finnish Foundation for Cardiovascular Research, the Finnish Medical Foundation and the Northern Finland Health Care Support Foundation.
Research article: Roosa Rahunen, Outi Kummu, Vesa Koivukangas, Heidi Hautajärvi, Jukka Hakkola, Jaana Rysä and Janne Hukkanen. Pregnane X Receptor‒4β‐Hydroxycholesterol Axis in the Regulation of Overweight‐ and Obesity‐Induced Hypertension. Journal of the American Heart Association. 2022;0:e023492. https://doi.org/10.1161/JAHA.121.023492