Abstract 20238: The Oncogenic Axis STAT3/Pim1 is a New Therapeutic Target for Human Pulmonary Arterial Hypertension
Pulmonary arterial hypertension (PAH) is a proliferative remodeling disease characterized by enhanced pulmonary artery smooth muscle (PASMC) proliferation and suppressed apoptosis. The sustainability of this phenotype requires the activation of NFAT (nuclear factor of activated T-cells). Because NFAT is implicated in several physiological processes (immune response), its inhibition will be associated with detrimental effects. A better understanding of the mechanism accounting for NFAT activation in PAH-PASMC is of a great therapeutic interest. Pim-1 is a kinase expressed in cancer and recognized as a strong “NFAT activator”. Pim1 is regulated by STAT3 (signal transducer and activator of transcription 3) activated by cytokines and growth factors (IL-6, PDGF), which are increased in PAH. We hypothesized that the STAT3/Pim-1 axis is involved in the pathogenesis of PAH. In both circulating cells, PASMC isolated from PAH patients (n=3 to 30) and experimental PAH models (monocrotaline M-PAH, chronic hypoxia CH-PAH), STAT3 /Pim-1 activation is increased (p<0.05 immunoblot & qRT-PCR) compared to control and positively correlates with both mean PA pressure (mPAP) and pulmonary vascular resistance (PVR) (p<0.05 n=30 patients). In human PAH-PASMC STAT3/Pim-1 axis activation accounts for NFAT expression and activation as STAT3 inhibition (siRNA) decreases NFAT expression (p<0.05 n=5 qRT-PCR) while Pim-1 inhibition decreases NFAT activation (p<0.05 n=5 luciferase & nuclear translocation assays). STAT3/Pim-1 inhibition: 1) increases apoptosis by 25% (n=150 p<0.05 TUNEL & TMRM) 2) decreases proliferation by 30% (PCNA & FLUO3 n=150 p<0.05). In vivo inhalation of Pim-1 siRNA in rats with M-PAH (n=10 p<0.05) supports a putative therapeutic effect of Pim-1 inhibition characterized by 1) a PA specific NFAT inhibition 2) decreased PA pressure, wall thickness and right ventricular hypertrophy. Finally, Pim1 KO mice were resistant to M&CH-PAH induction (n=20). We demonstrated that the inhibition of the STAT3/Pim-1 axis in human and experimental PAH is a novel and attractive therapeutic strategy to reverse PAH. Moreover, the significant correlation between Pim-1 expression and both mPAP and PVR suggests that Pim-1 is also a new biomarker of PAH.
- © 2010 by American Heart Association, Inc.