Abstract
Similarly to cancer, pulmonary arterial hypertension (PAH) is characterized by a pro-proliferative and anti-apoptotic phenotype. In PAH, pulmonary artery smooth muscle cells (PASMC) proliferation is enhanced and apoptosis suppressed. The sustainability of this phenotype requires the activation of pro-survival transcription factors like STAT3 and NFAT. Presently, clinically available drugs able to efficiently and safely inhibit this axis are not available. We hypothesized that Plumbagin (PLB), a natural vegetal organic compound known to block STAT3 in cancer cells, reverses experimental pulmonary hypertension. We demonstrated, in vitro, using human PAH-PASMC, that PLB inhibits the activation of a STAT3/NFAT axis, increasing voltage-gated K+ current, BMPR2 and decreasing [Ca2+]I, ROCK1 and IL-6, contributing to the inhibition of PAH-PASMC proliferation and resistance to apoptosis (PCNA, TUNEL, Ki67, Anexine V). In vivo, PLB oral administration decreases distal PA remodeling, mean PA pressure and right ventricular hypertrophy without affecting systemic circulation in both monocrotaline- and Sugen/chronic hypoxia-induced PAH in rats.
This study demonstrates that STAT3/NFAT axis can be therapeutically targeted by PLB in human PAH-PASMC and experimental PAH rat models. Thus, PLB could be considered as a specific and attractive future therapeutic strategy for PAH.
- ERS