European Respiratory Society

Plumbagin reverses proliferation and resistance to apoptosis in experimental PAH

Audrey Courboulin, Marjorie Barrier, Tanya Perreault, Pierre Bonnet, Veronique L. Tremblay, Roxane Paulin, Ève Tremblay, Caroline Lambert, Maria H. Jacob, Sandra N. Bonnet, Steeve Provencher, Sébastien Bonnet


Like cancer, pulmonary arterial hypertension (PAH) is characterised by a pro-proliferative and anti-apoptotic phenotype. In PAH, pulmonary artery smooth muscle cell (PASMC) proliferation is enhanced and apoptosis suppressed. The sustainability of this phenotype requires the activation of pro-survival transcription factors, such as signal transducer and activator of transcription (STAT)3 and nuclear factor of activated T-cells (NFAT). There are no drugs currently available that are able to efficiently and safely inhibit this axis. We hypothesised that plumbagin (PLB), a natural organic compound known to block STAT3 in cancer cells, would reverse experimental pulmonary hypertension.

Using human PAH-PASMC, we demonstrated in vitro that PLB inhibits the activation of the STAT3/NFAT axis, increasing the voltage-gated K+ current bone morphogenetic protein receptor type II (BMPR2), and decreasing intracellular Ca2+ contentration ([Ca2+]i), rho-associated coiled-coil containing protein kinase (ROCK)1 and interleukin (IL)-6, contributing to the inhibition of PAH-PASMC proliferation and resistance to apoptosis (proliferating cell nuclear antigen (PCNA), TUNEL, Ki67 and anexine V). In vivo, PLB oral administration decreases distal pulmonary artery remodelling, mean pulmonary artery pressure and right ventricular hypertrophy without affecting systemic circulation in both monocrotaline- and sugen/chronic hypoxia-induced PAH in rats.

This study demonstrates that the STAT3/NFAT axis can be therapeutically targeted by PLB in human PAH-PASMC and experimental PAH rat models. Thus, PLB could be considered a specific and attractive future therapeutic strategy for PAH.


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  • Support Statement

    S. Bonnet has been funded for this work by the Canadian Institutes of Health Research (CIHR). S. Bonnet holds the position of Canada Research Chair. M.H. Jacob was supported by CAPES (the Brazilian Research Agency). A. Courboulin and R. Paulin are recipients of graduate scholarships from La Société Qébécoise d'Hypertension Artérielle (SQHA).

  • Statement of Interest

    None declared.

  • Received May 18, 2011.
  • Accepted December 15, 2011.
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