Abstract 14222: NFAT5 Controls Vessel Wall Remodeling During Pulmonary Artery Hypertension
Introduction: Pulmonary artery hypertension (PAH) is a life-threatening cardiovascular disease with poor prognosis that is caused inter alia by constriction and inward remodeling of pulmonary arteries eliciting an increase in pulmonary blood pressure. We recently reported that a pressure-induced increase in biomechanical stress triggers the transcriptional activity of nuclear factor of activated T-cells 5 (NFAT5) in arterial smooth muscle cells (SMC) to control the expression of tenascin-C - a molecular marker of PAH.
Hypothesis: NFAT5 activity promotes arterial remodeling during PAH.
Methods & Results: Experimental PAH was evoked by exposing NFAT5flx/flx or inducible SMC-specific NFAT5-deficient mice (NFAT5-/-) to hypoxia for 21 days. These conditions elevated the Fulton index (right/(left + septum) ventricular weight; 0.25 (control) vs. 0.42 (PAH), p<0.001, n=8) and led to a weight loss (16%, p<0.05, n=8) of NFAT5flx/flx but not NFAT5-/- mice. Telemetric assessment of the baseline blood pressure of NFAT5-/- and NFAT5flx/flx mice thereby revealed no significant difference. On the molecular level, PAH triggered the expression of NFAT5 in vascular but not airway SMC of NFAT5flx/flx mice (3.36-fold, p<0.01, n=5) and was accompanied with thickening of pulmonary arterial walls (1.85-fold, p<0.001, n=5) as well as local accumulation of tenascin-C (2.32-fold, p<0.01, n=5). Upon SMC-specific genetic ablation of NFAT5 all of these effects were abolished. In vitro studies indicated that blocking palmitoylation processes by Etomoxir inhibits nuclear entry and transcriptional activity of NFAT5 by 80 percent (p<0.05, n=5) in arterial SMCs exposed to biomechanical stretch as it occurs during PAH. Further mechanistic studies showed that phosphomimetic mutations at S1197, phosphodeficient mutations at T143 or treatment with the protein kinase inhibitor dasatinib blocked nuclear translocation and transcriptional activity of NFAT5.
Conclusions: Collectively, our findings indicate that chronic exposure of arterial SMCs to hypertensive wall stress activates NFAT5 and controls its entry into the nucleus. During PAH, the transcriptional targets of NFAT5 support the remodeling of pulmonary arteries which may contribute to right heart failure.
Author Disclosures: M. Zappe: None. W. Neuhofer: None. M. Hecker: None. T. Korff: None.
- © 2016 by American Heart Association, Inc.