Obesity is a common comorbidity for pulmonary arterial hypertension (PAH). Additionally, oestrogen and its metabolites are risk factors for the development of PAH. Visceral adipose tissue (VAT) is a major site of oestrogen production; however, the influence of obesity-induced changes in oestrogen synthesis and metabolism on the development of PAH is unclear. To address this we investigated the effects of inhibiting oestrogen synthesis and metabolism on the development of pulmonary hypertension (PH) in male and female obese mice
We depleted endogenous oestrogen in leptin deficient (ob/ob) mice with the oestrogen inhibitor anastrozole (ANA) and determined the effects on the development of PH, plasma oestradiol and urinary 16α-hydroxyestrone (16αOHE1). Oestrogen metabolism through CYP1B1 was inhibited with 2,2′,4,6′-tetramethoxystilbene (TMS).
Ob/ob mice spontaneously develop PH, pulmonary vascular remodelling and increased reactive oxygen species (ROS) production in the lung; these effects were attenuated by ANA. Oestradiol levels were decreased in obese male mice; however, VAT CYP1B1 and 16αOHE1 levels were increased. TMS also attenuated PH in male ob/ob mice. Intra-thoracic fat from ob/ob mice and VAT conditioned media produce 16αOHE1 and can contribute to oxidative stress; effects that are attenuated by both ANA and TMS.
Obesity can induce PH and changes in oestrogen metabolism, resulting in increased production of 16αOHE1 from VAT that contributes to oxidative stress. Oestrogen inhibitors are now in clinical trials for PAH. This study has translational consequences as it suggests that oestrogen inhibitors may be especially beneficial in treating obese individuals with PAH.
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Conflict of interest: Dr. Mair has nothing to disclose.
Conflict of interest: Dr. Harvey has nothing to disclose.
Conflict of interest: Dr. Henry has nothing to disclose.
Conflict of interest: Dr. Hillyard has nothing to disclose.
Conflict of interest: Dr. Nilsen has nothing to disclose.
Conflict of interest: Dr. MacLean has nothing to disclose.