Rahunen, R., Kummu, O., Koivukangas, V., Hautajärvi, H., Hakkola, J., Rysä, J., & Hukkanen, J. (2022). Pregnane x receptor‒4β‐hydroxycholesterol axis in the regulation of overweight‐ and obesity‐induced hypertension. Journal of the American Heart Association, 11(6), e023492. https://doi.org/10.1161/JAHA.121.023492
Pregnane X receptor‒4β‐hydroxycholesterol axis in the regulation of overweight‐ and obesity‐induced hypertension
|Author:||Rahunen, Roosa1,2,3; Kummu, Outi2,3,4; Koivukangas, Vesa3,5;|
1Research Unit of Internal Medicine, University of Oulu, Finland
2Biocenter Oulu, University of Oulu, Finland
3Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Finland
4Research Unit of Biomedicine, Pharmacology and Toxicology, University of Oulu, Finland
5Department of Surgery, Oulu University Hospital and University of Oulu, Finland
6Admescope Ltd., Oulu, Finland
7Finnish Customs Laboratory, Finland
8School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland
|Online Access:||PDF Full Text (PDF, 0.6 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe2022051034139
John Wiley & Sons,
|Publish Date:|| 2022-05-10
Background: Mechanisms mediating hypertensive effects of overweight and obesity have not been fully elucidated. We showed previously that activation of pregnane X receptor (PXR) by rifampicin elevates 24‐hour blood pressure (BP) and plasma 4β‐hydroxycholesterol (4βHC), agonist for liver X receptor (LXR).
Methods and Results: In combined “PXR activation data set” (n=62) of 4 clinical trials, 1 week rifampicin dosing increased office systolic BP (SBP) by 3.1 mm Hg, DBP 1.8 mm Hg, and mean arterial pressure 2.2 mm Hg in comparison with placebo (P<0.01). Plasma 4βHC had negative correlation with SBP both in rifampicin (r=−0.46, P=0.0002) and placebo (r=−0.45, P=0.0003) arms, although 4βHC was elevated >3‐fold by rifampicin. In “non‐intervention data set” (n=102) of patients with obesity and healthy volunteers (body mass index, 19.2–55.2 kg/m2), 4βHC had negative correlations (P<0.00001) with office SBP (r=−0.51), diastolic BP (r=−0.50), and mean arterial pressure (r=−0.54). Lean women had higher 4βHC than men, with increasing weight repressing 4βHC (r=−0.62, P<0.00001) in both sexes. In multiple linear regression analysis, the only statistically significant predictor for SBP was 4βHC. Six‐day PXR agonist dosing elevated SBP in rats (n=7–8/group). PXR activation elevated 4βHC and after PXR agonist was withdrawn and elevated 4βHC was left to act alone, SBP was reduced on days 7 to 14 in comparison with control rats.
Conclusions: PXR activation elevates SBP. Elevated circulating 4βHC lowers SBP in rats, and higher 4βHC is an independent predictor of lower SBP in humans. PXR‐4βHC‐LXR is novel BP‐regulating pathway deregulated in overweight and obesity by repressed 4βHC, with implications for sex‐specific BP regulation.
Registration: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT00985270, NCT01293422, NCT01690104, NCT02329405, and NCT01330251.
Journal of the American Heart Association
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
3121 General medicine, internal medicine and other clinical medicine
The trials and studies were financially supported by grants from the Diabetes Research Foundation, the Finnish Foundation for Cardiovascular Research, the Northern Finland Health Care Support Foundation, Finnish Government Grants for Health Research, and the Finnish Medical Foundation.
© 2022 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.