Dichloroacetate treatment partially regresses established pulmonary hypertension in mice with SM22 -targeted overexpression of the serotonin transporter (original) (raw)

and in experimental models including mice with SM22␣-targeted overexpression of the serotonin transporter (5-HTT). The mechanisms underlying these abnormalities, however, remain unknown. Dichloroacetate (DCA) inhibits chronic hypoxia-or monocrotaline-induced PAH by inhibiting nuclear factor of activated T-cells (NFAT)c2 and increasing Kv1.5. Therefore, we hypothesized that DCA could regress established PAH in SM22-5-HTT ؉ mice. We evaluated pulmonary hemodynamics, vascular remodeling, NFATc2, and Kv1.5 protein in 20-wk-old SM22-5-HTT ؉ or wild-type mice treated for 1, 7, and 21 d with DCA, cyclosporine-A (NFAT inhibitor), or vehicle. DCA partially reversed PAH in SM22-5-HTT ؉ mice by decreasing proliferation and increasing apoptosis in muscularized PAs. Furthermore, serotonin 10 ؊8 -10 ؊6 M) dose-dependently increased PA-smooth muscle cell (PA-SMC) proliferation in culture (EC 50 ‫01؋79.0؍‬ ؊7 M) and DCA (5؋10 ؊4 M) vs. PBS markedly reduced the growth of PA-SMC from IPAH and control patients treated with the highest dose of serotonin by 50 and 30%, respectively. Finally, although serotonin induces NFATc2 activation in PA-SMCs, inhibition of NFATc2 alone with cyclosporine-A was not sufficient for reversing PAH in this model. Our results support the possibility that DCA may be an interesting agent for investigation in patients with PAH.-Guignabert, C., Tu, L., Izikki, M., Dewachter, L., Zadigue, P., Humbert, M., Adnot, S., Fadel, E., Eddahibi, S. Dichloroacetate treatment partially regresses established pulmonary hypertension in mice with SM22␣-targeted overexpression of the serotonin transporter. FASEB J. 23, 000 -000 (2009). www.fasebj.org Key Words: pulmonary vascular remodeling ⅐ serotonin pathway ⅐ NFAT/Kv1.5 axis ⅐ PDK inhibitor ⅐ Bcl-2/Bax ratio