Dichloroacetate treatment partially regresses established pulmonary hypertension in mice with SM22alpha-targeted overexpression of the serotonin transporter. - Archive ouverte HAL Access content directly
Journal Articles FASEB Journal Year : 2009

Dichloroacetate treatment partially regresses established pulmonary hypertension in mice with SM22alpha-targeted overexpression of the serotonin transporter.

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Abstract

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 SM22alpha-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)=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.
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Dates and versions

inserm-00499630 , version 1 (11-07-2010)

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Christophe Guignabert, Ly Tu, Mohamed Izikki, Laurence Dewachter, Patricia Zadigue, et al.. Dichloroacetate treatment partially regresses established pulmonary hypertension in mice with SM22alpha-targeted overexpression of the serotonin transporter.: Efficacy Of DCA Treatment In SM22-5-HTT+ Mice. FASEB Journal, 2009, 23 (12), pp.4135-47. ⟨10.1096/fj.09-131664⟩. ⟨inserm-00499630⟩
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