Joshua P. Dignam, Smriti Sharma, Gregor Aitchison, Ayman Gebril, Ioannis Stasinopoulos, Sofia Laforest, Chelbi Coyle, Ruth Andrew, Natalie Z. M. Homer, Sébastien Bonnet, Sandra Breuils-Bonnet, Martin Wabitsch, Margaret R. MacLean
University of Strathclyde. Queen Mary University of London. Medical University of Vienna. University of Edinburgh. Laval University. Ulm University Medical Center.
United Kingdom, Austria, Canada and Germany
British Journal of Pharmacology
Br J Pharmacol 2025;
DOI: 10.1111/bph.70244
Abstract
Background and purpose: The contribution of obesity to pulmonary arterial hypertension (PAH) pathophysiology remains poorly understood. Adipose tissue synthesises estrogens via cytochrome P450 (CYP) 19A1 (aromatase), whereas circulating estrogens are metabolised in the lung by CYP1A1. This study investigated whether obesity predisposes to PAH through enhanced estrogen synthesis and metabolism.
Experimental approach: A normoxic, two-hit, rat model of obesity-associated pulmonary hypertension (PH) was developed, combining Sugen 5416 (Sugen, Su) with a high-fat diet (HFD). Estrogen levels in SuHFD rat plasma and epicardial adipose tissue (EAT) from PAH patients were quantified using LC-MS/MS. CYP1A1 expression was assessed in lung and cardiac adipose tissue from SuHFD rats and PAH patients. The therapeutic potential of the CYP1A1 inhibitor hesperetin was evaluated in vivo. Complementary studies used pulmonary artery smooth muscle cells (PASMCs) from PAH patients and Simpson-Golabi-Behmel syndrome (SGBS) adipocytes.
Key results: HFD-fed rats of both sexes developed mild PH, which Sugen moderately exacerbated. EAT from PAH patients exhibited up-regulated aromatase and CYP1A1 expression, along with elevated estrogen levels. Circulating estrone was increased in male SuHFD rats. Pulmonary CYP1A1 expression was elevated in SuHFD rats and PAH patients. Hesperetin attenuated obesity-associated PH, reducing CYP1A1 expression in SuHFD rat lungs and PAH PASMCs. CYP1A1 induction in female SuHFD rat pericardial adipose tissue and Sugen-treated SGBS adipocytes was also tempered.
Conclusion and implications: These findings implicate augmented estrogen production by adipose tissue and elevated pulmonary CYP1A1 expression in the pathogenesis of obesity-associated PH. CYP1A1 may represent a novel therapeutic target in obese PAH patients.
Category
Environmental Factors Associated with Pulmonary Vascular Disease
Animal Models of Pulmonary Vascular Disease and Therapy
Vascular Cell Biology and Mechanisms of Pulmonary Vascular Disease
Class I. Drug-induced and Toxin-induced Pulmonary Hypertension
Medical Therapy. Efficacy or Lack of Efficacy
Age Focus: No Age-Related Focus
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: Yes