Cytochrome P450 1A1 influences obesity-induced pulmonary hypertension.

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.