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

Christophe Guignabert^*,,1, Ly Tu^*,,2, Mohamed Izikki^*,,2, Laurence Dewachter^*, Patricia Zadigue, Marc Humbert^*,, Serge Adnot, Elie Fadel^*, and Saadia Eddahibi^*,

^* INSERM Unity "Pulmonary Hypertension: Pathophysiology and Innovative Therapies," Centre Chirurgical Marie Lannelongue, Université Paris-Sud 11, Le Plessis-Robinson, France;

INSERM U955, Institut Mondor de Recherche Biomédicale, Créteil, France;

UPRES EA2705, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France; and

INSERM U764, Hôpital Antoine-Béclère, AP-HP, Clamart, France

¹ Correspondence: INSERM Unity "Pulmonary Hypertension: Pathophysiology and Innovative Therapies," Centre Chirurgical Marie Lannelongue, 133 avenue de la Résistance, 92350 Le Plessis-Robinson, France. E-mail: christophe.guignabert{at}inserm.fr

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-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=0.97x10^–7 M) and DCA (5x10^–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.

Key Words: pulmonary vascular remodeling • serotonin pathway • NFAT/Kv1.5 axis • PDK inhibitor • Bcl-2/Bax ratio