Metformin reverses development of pulmonary hypertension via aromatase inhibition

Afshan Dean, Margaret Nilsen, Lynn Loughlin, Ian P. Salt, Margaret R. MacLean

Research output: Contribution to journalArticle

34 Citations (Scopus)
10 Downloads (Pure)

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.

Original languageEnglish
Pages (from-to)446-454
Number of pages9
JournalHypertension
Volume68
Issue number2
DOIs
Publication statusPublished - 1 Aug 2016

    Fingerprint

Keywords

  • AMP-activated protein kinase
  • aromatase
  • estrogen
  • metformin
  • pulmonary hypertension

Cite this