Abstract 762: NFAT Activation in Pulmonary Arterial Hypertension; a Missing Link in the Ionic (K+ Channel Downregulation), Inflammatory (T-cell activation) Remodeling and a Novel Therapeutic Target
Pulmonary Arterial Hypertension (PAH) is characterized by an apoptosis-resistant, proliferative and inflammatory vascular remodeling; it is also associated with a selective down-regulation of Kv1.5, a K+ channel that regulates the membrane potential of pulmonary artery smooth muscle cells (PASMC). This results in PASMC depolarization, causing
increased influx of [Ca++]i from voltage-gated Ca++ channels and enhanced proliferation and
increase in [K]i which suppresses apoptosis by tonically inhibiting caspases.
The mechanism of Kv1.5 down-regulation remains unknown. We hypothesized that Kv1.5 is regulated by NFAT, a calcineurin-sensitive transcription factor. We studied PASMC (normoxic or hypoxic), lungs and blood from 11 PAH and 12 healthy patients. Compared to normal, hypoxic and PAH PASMC had decreased Kv current, decreased Kv1.5 expression and ~40% increase in [Ca++]i. Hypoxic and PAH PASMC and lungs showed activation of NFAT1 (nuclear translocation) compared to normal. Inhibition of NFAT1 by VIVIT (a competing peptide) or cyclosporine, normalized the hypoxic and PAH PASMC, increasing Kv1.5 and Kv current and decreasing [Ca++]i; resulting in decreased proliferation (PCNA) and increased apoptosis (TUNEL) in vitro. In vivo, cyclosporine treatment for 3 weeks reversed monocrotaline-PAH in rats (n=10), improving hemodynamics, right ventricular and PA medial hypertrophy. NFAT1 levels were increased in peripheral blood cells in PAH compared to healthy patients and CD3-positive lymphocytes with activated NFAT1 were seen in the vessel wall in PAH but not normal lungs. NFAT1 might regulate the anti-apoptotic, proliferative and inflammatory vascular remodeling and be a novel therapeutic target in PAH.