Abstract 17741: Dehydroepiandrosterone (DHEA) Reverses Pulmonary Hypertension Through Inhibition of the Stat3/Pim1/NFAT Axis
Background: Pulmonary Arterial Hypertension (PAH) are obstructive vasculopathy characterized by enhanced pulmonary artery smooth muscle cells (PASMC) proliferation and suppressed apoptosis. We recently described that this phenotype is associated with Signal Transducer and Activator of Transcription3 (STAT3)/ Provirus Integration site for Moloney murine leukemia virus (Pim1)/Nuclear Factor of Activated T-cells (NFAT) axis activation, resulting in proliferation and apoptosis resistance. Dehydroepiandrosterone (DHEA) is a steroid hormone known to reverse vascular remodeling. We hypothesized that DHEA is able to reverse Human Pulmonary Hypertension by inhibiting STAT3/Pim1/NFAT axis.
Methods/Results: Using PASMC isolated from patient with PAH (n=3), we demonstrated that DHEA decreases STAT3 activation (Western Blot, luciferase assay). STAT3 inhibition resulted in a significant reduction in Pim1 and NFATc2 expression/activation (qRT-PCR; western blot and ChIP-PCR n=3;p<0.05) and upregulation of BMPR2. STAT3/Pim1/NFAT axis inhibition along with the upregulation of BMPR2 by DHEA is associated with 1) BAD/Bcl2-dependent depolarization of the mitochondrial membrane potential (TMRM, n=150 p<0.05) increasing apoptosis by 25% (TUNEL, annexin V; n=150 p<0.05); 2) decreased [Ca2+]i (FLUO3AM n=150, p<0.05) and decreased proliferation by 30% (PCNA). Finally, in vivo DHEA improves experimental PAH (monocrotaline rats) by decreasing mean PA pressure, RV hypertrophy. These effects were associated with the inhibition of STAT3, Pim1 and NFAT and the upregulation of BMPR2.
Conclusions: We demonstrated that DHEA reverses Pulmonary Hypertension by inhibiting the Stat3/Pim1/NFATc2 axis resulting in BMPR2 upregulation. After a conclusive phase II clinical trials on 12 PAH patients, DHEA has been moved to phase III trials in human.
- © 2010 by American Heart Association, Inc.