Metformin Reverses Development of Pulmonary Hypertension via Aromatase Inhibition

Abstract

H uman pulmonary arterial hypertension (PAH) is a progressive disease of the pulmonary vasculature, which often leads to right heart failure. PAH is characterized by elevated pulmonary pressure (>25 mm Hg at rest), vascular remodeling, and occlusive pulmonary vascular lesions. Although survival rates are improving slowly; there remains an unacceptably poor survival rate. 1 Females are more susceptible to PAH than males, as indicated in, for example, the REVEAL (Registry to Evaluate Early and Long-Term PAH Disease Management) registry where ≈80% of the patients registered were female.2,3 However, male patients have a poorer survival rate than females, implicating sex hormones in both PAH susceptibility and survival. 4 Consequently, the role of estrogens in PAH has been accumulating significant interest. [5][6][7][8] There is an estrogen paradox however as while exogenous estrogen may be protective against experimental pulmonary hypertension (PH) and right ventricular (RV) hypertrophy in rodent models, [9][10][11][12] endogenous estrogen is causative in female animal models. [13][14][15][16][17] Estrogen is synthesized from testosterone through the enzyme aromatase and inhibition of aromatase attenuates experimental PH but only in females. 17 Estrogen can be metabolized through the cytochrome p450 1B1 (CYP1B1) enzyme to form the mitogenic 16α-hydroxyestrone, a metabolite established to be pathogenic in PH. 16 Furthermore, single-nucleotide polymorphisms of CYP1B1 have been recently identified to be associated with PH and indicated to play a key role in sexual dimorphism in RV failure. 18 One transcription factor for CYP1B1 is the aryl hydrocarbon receptor (AhR), suppression of which has been shown to be antiproliferative (protective) in PH. 19 Metformin is a well-established drug for use in type 2 diabetes mellitus 20,21 and has been demonstrated to activate AMP-activated protein kinase (AMPK) in many tissues, although AMPK does not underlie the hypoglycemic actions of metformin. 22 AMPK is a ubiquitously expressed serine/threonine protein kinase, which plays a critical role in cellular and organ metabolism. 23,24 In breast cancer and polycystic ovarian syndrome, the therapeutic effects of metformin involves the enhancement of the AMPK pathway and inhibition of the nuclear translocation of cyclic AMPresponsive element binding protein-regulated transcription coactivator 2 (CRTC2). CRTC2 (a downstream target of AMPK) can bind to the PII promoter site of the aromatase Abstract-Females are more susceptible to pulmonary arterial hypertension than males, although the reasons remain unclear. The hypoglycemic drug, metformin, is reported to have multiple actions, including the inhibition of aromatase and stimulation of AMP-activated protein kinase. Inhibition of aromatase using anastrazole is protective in experimental pulmonary hypertension but whether metformin attenuates pulmonary hypertension through this mechanism remains unknown. We investigated whether metformin affected aromatase activity and if it could r...

Anastrozole in Pulmonary Arterial Hypertension. A Randomized, Double-Blind, Placebo-controlled Trial

“…Administration of AN after Sugenhypoxia administration reduced RV systolic pressure, pulmonary vascular remodeling, and RV mass in the female animals (in whom it also reduced E2 levels). This group also showed that metformin had a similar effect via aromatase inhibition (17). Small muscular pulmonary arterioles also expressed estrogen receptor (ER)-a in the serotonin transporter overexpressing animal model, the blockade of which reduced RV systolic pressure (16).…”

“…Finally, recent studies have shown that aromatase is produced in the smooth muscle cells of the small muscular pulmonary arteries in both female animal models of PH and in women with PAH (15,16). Administration of the aromatase inhibitor anastrozole (AN) reduced pulmonary arterial pressures, pulmonary vascular changes, and indexes of RV hypertrophy in experimental PH (15,16); metformin had similar effects via aromatase inhibition (17). Together, experimental and observational evidence suggests that limiting E2 exposure via aromatase inhibition may be a therapeutic strategy in PAH, but the effects of hormonal manipulation have not been tested in patients with pulmonary vascular disease.…”

Pulmonary vascular dysfunction in metabolic syndrome

“…Metformin administration also decreased RVSP in Sugen/hypoxic‐induced PH rats (Dean et al . ) and Sugen‐treated Zucker fatty rats (Lai et al . ).…”

Update on novel targets and potential treatment avenues in pulmonary hypertension

“…However, there was no benefit of metformin therapy in older rats with established PH-HFpEF. In the female rat SuHx model of PH, metformin therapy reversed elevated P PA and vascular remodeling (56). In this study, metformin had several effects on SuHx lungs, including increased AMPK activity, decreased aromatase and estrogen levels and decreased PASMC proliferation, suggesting that one of the downstream effects of metformin-induced AMPK activation is to regulate the sex hormone axis via aromatase inhibition.…”