Abstract 3463: Tumor Necrosis Factor-α Inhibits Pyruvate Dehydrogenase Causing Pulmonary Arterial Hypertension
The apoptosis resistance of pulmonary artery smooth muscle cell (PASMC) that characterizes pulmonary arterial hypertension (PAH) is associated with: decreased mitochondrial pyruvate dehydrogenase (PDH) activity, mitochondrial hyperpolarization (increased ΔΨm), decreased mitochondrial reactive oxygen species (mROS), down-regulation of plasmalemmal potassium channels (Kv1.5), increased [Ca++]i and activation of the transcription factor nuclear factor of activated T-cells (NFAT). The PDH activator Dichloroacetate (DCA) reverses most known animal models of PAH, suggesting a critical role of PDH in PAH. Inflammatory cells are present within and around the PA wall and increased cytokines (including TNF-α) are found in the serum of PAH patients but it is unknown whether they contribute to PAH development. We hypothesized that TNF-α inhibits PASMC PDH activity causing PAH and that TNF-α inhibition reverses the disease. We studied normal human PASMC treated with recombinant human TNF-α (rhTNF-α, 1ug/mL) for 96h. rhTNF-α decreased PDH activity, increased ΔΨm, decreased mROS, decreased K+ current, down-regulated Kv1.5, increased [Ca++]i and activated NFAT. In vivo, the clinically used TNF-α antagonist Etanercept (0.6mg/Kg SC, 2x week, for 3weeks) prevented and reversed monocrotaline-induced PAH in rats (catheterization measuring mean PA pressure, ECHO, right ventricular hypertrophy). In the reversal protocol the control vs treated groups (n=8–10) showed: mean PAP 39±3 vs 21±1 mmHg, RV/LV+ septum ratio 0.46±0.01 vs 0.35±0.03, %medial thicknes 52±2 vs 42±4. (p<0.05 for all). Resistance PAs from Etanercept-treated rats had decreased PASMC proliferation (PCNA) and increased apoptosis (TUNEL) resulting in decreased vascular remodeling. We show for the first time that TNF-α can inhibit PDH activity in normal human PASMC inducing a PAH phenotype in vitro and that it can be therapeutically targeted in vivo. Our work supports the use of specific anti-inflammatory therapies for PAH and might help explain why inflammatory disease-associated PAH is the most severe form of the disease.