Obesity alters oestrogen metabolism and contributes to pulmonary arterial hypertension

Abstract

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 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 pulmonary hypertension, plasma oestradiol and urinary 16α-hydroxyestrone (16αOHE1). Oestrogen metabolism through cytochrome P450 1B1 (CYP1B1) was inhibited with 2,2′,4,6′-tetramethoxystilbene (TMS).ob/ob mice spontaneously develop pulmonary hypertension, pulmonary vascular remodelling and increased reactive oxygen species 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 pulmonary hypertension 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 pulmonary hypertension 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.

Association of Body Mass Index With Postoperative Early Adverse Outcomes in Acute Type a Aortic Dissection Patients in Fujian Province, China: A Retrospective Study

“…In this study, the group with a higher proportion of smokers has a higher incidence of prolonged MV. 2The adipose tissue creates a number of estrogens in overweight and obese patients that play an important role in pulmonary hypertension and remodeling [37] . It generally focuses on the changes in pulmonary and chest wall structures, which led to the increase of residual lung volume and chest wall impedance, a decrease of lung compliance and ventilation driving force, and abnormal ventilation-perfusion [38] .…”

Obesity, estrogens and adipose tissue dysfunction – implications for pulmonary arterial hypertension

“…However, we have shown that CYP1B1 is upregulated in white adipose tissue in obese mice and is involved in mediating the production and release of the mitogenic estrogen metabolite 16OHE1. 7 Obesity, estrogen metabolism and PAH Estrogen metabolism also plays a key role in PAH. As described above, there is an abundance of CYP1B1 in adipose tissue.…”

“…On the other hand, the proproliferative estrogen metabolite 16OHE1 induces pulmonary vascular remodelling and may promote insulin resistance in PAH. 7,9 For example, Fessel et al 9 found that treating BMPR2-mutant vascular smooth muscle cells with 16OHE1 significantly decreased mobilization of the glucose transporter Glut4 in response to insulin and expression of PPAR-g and lipid transporter CD36. Based on a proof-of-concept study, 16OHE2 has recently been hypothesized to be a mediator of PAH.…”

“…However, we have shown that CYP1B1 is upregulated in white adipose tissue in obese mice and is involved in mediating the production and release of the mitogenic estrogen metabolite 16OHE1. 7 …”

“… 5 Of interest, adipose tissue synthesizes estrogen, and adipose tissue expansion in obesity is known to contribute to development of estrogen-sensitive breast cancer. 6 Adipose tissue contains high levels of the estrogen-metabolizing enzyme cytochrome P450 1B1 (CYP1B1), and in obese mice, thoracic adipose tissue produces 16α-hydroxyestrone (16OHE1), 7 a known mitogen in the pulmonary circulation. 8 It is also thought that 16OHE1 can increase the penetrance of mutations in bone morphogenetic protein receptor 2 (BMPR2) both experimentally and clinically.…”