Metformin reverses development of pulmonary hypertension via aromatase inhibition

Dean, A., Nilsen, M., Loughlin, L., Salt, I. P. and MacLean, M. R. (2016) Metformin reverses development of pulmonary hypertension via aromatase inhibition. Hypertension, 68(2), pp. 446-454. (doi:10.1161/HYPERTENSIONAHA.116.07353) (PMID:27296990)

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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 reduce the development of pulmonary hypertension in the sugen 5416/hypoxic rat model. We also investigated its influence on proliferation in human pulmonary arterial smooth muscle cells. Metformin reversed right ventricular systolic pressure, right ventricular hypertrophy, and decreased pulmonary vascular remodeling in the rat. Furthermore, metformin increased rat lung AMP-activated protein kinase signaling, decreased lung and circulating estrogen levels, levels of aromatase, the estrogen metabolizing enzyme; cytochrome P450 1B1 and its transcription factor; the aryl hydrocarbon receptor. In human pulmonary arterial smooth muscle cells, metformin decreased proliferation and decreased estrogen synthesis by decreasing aromatase activity through the PII promoter site of Cyp19a1. Thus, we report for the first time that metformin can reverse pulmonary hypertension through inhibition of aromatase and estrogen synthesis in a manner likely to be mediated by AMP-activated protein kinase.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:MacLean, Professor Margaret and Loughlin, Mrs Lynn and Nilsen, Mrs Margaret and Dean, Dr Afshan and Salt, Dr Ian
Authors: Dean, A., Nilsen, M., Loughlin, L., Salt, I. P., and MacLean, M. R.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Hypertension
Publisher:American Heart Association
ISSN:0194-911X
ISSN (Online):1524-4563
Published Online:13 June 2016
Copyright Holders:Copyright © 2016 American Heart Association
First Published:First published in Hypertension 68(2): 446-454
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
573731Gender and the development of pulmonary arterial hypertension: regulation of genes from mouse to manMargaret MacLeanBritish Heart Foundation (BHF)RG/11/7/28916RI CARDIOVASCULAR & MEDICAL SCIENCES
614801Oestrogen synthesis and metabolism in pulmonary arterial hypertensionMargaret MacLeanBritish Heart Foundation (BHF)PG/13/7/29913RI CARDIOVASCULAR & MEDICAL SCIENCES