Dichloroacetate treatment partially regresses established pulmonary hypertension in mice with SM22α-targeted overexpression of the serotonin transporter

Voltage-gated potassium (Kv)1.5 is decreased in pulmonary arteries (PAs) of patients with idiopathic pulmonary arterial hypertension (IPAH) and in experimental models including mice with SM22 alpha-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 (EC50 = 0.97 x 10(-7) M) and DCA (5 x 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 alpha-targeted overexpression of the serotonin transporter. FASEB J. 23, 4135-4147 (2009). www.fasebj.org