Abstract
Background: Epidemiologic studies have revealed the female predominance in the morbidity of idiopathic PAH (pulmonary arterial hypertension) in the world, suggesting involvement of sex hormones in the pathogenesis of PAH. Recent studies have identified a role of bone morphogenetic protein (BMP) signaling in the pathogenesis of PAH and we reported that BMP signaling in pulmonary arterial endothelial cells (PAEC) was attenuated under hypoxic condition in vitro and in vivo.
Purpose: The aim is to investigate effects of estradiol (E) and testosterone (T) on the BMP signaling in PAEC and analyze their mechanisms.
Materials and methods: PAEC were cultured and incubated with β-estradiol (10-7M), testosterone (10-8M), or vehicle under 1%O2 (hypoxia) and 21%O2 (normoxia). BMP signaling including Smad1/5/8, phosphorylated (p-) Smad1/5/8, and Id1 was examined by western blotting and quantitative RT-PCR. The effects of HIF (hypoxia-inducible factor) -1α expression on the BMP signaling were also examined.
Results: Under normoxia, p-Smad1/5/8 protein and Id1 mRNA were augmented 1.6 and 1.5-fold by E, but suppressed 0.3 and 0.4 -fold by T. Under hypoxia, conversely, p-Smad1/5/8 protein and Id1 mRNA were suppressed 0.5 and 0.4-fold by E, but augmented 3.2 and 2.4 -fold by T. HIF-1α accumulation led to alterlation of BMP signaling similar to hypoxia, whereas HIF-1α inhibitor altered the signaling similar to normoxia.
Discussion: Sex hormones could change BMP signaling in PAEC depending on oxygen concentration. Our observations provide the new mechanism how sex hormone affects on BMP signaling, and sex hormones may be novel therapeutic targets in the treatment of PAH.
- © 2011 ERS