Abstract 15994: Inhibition of Nuclear Factor-κB mediated Inflammation Reverses Fibrosis and Improves Right Ventricular Function in Rats With Pulmonary Artery Banding
Introduction: In patients with pulmonary arterial hypertension (PAH), right ventricular (RV) dysfunction predicts poor prognosis. Although, nuclear factor-κB (NF-κB) is excessively activated in RV of PAH, how it affects RV function remains unknown. We hypothesized that the RV pressure overload activates NF-κB-mediated inflammation and deteriorates RV function.
Methods: We banded the main pulmonary artery (PAB) using 18-gauge needle in Sprague-Dawley rats (BW: 180-220g). We evaluated hemodynamics and inflammatory responses of RV at Day1, 3, 7, 14 and 28 after PAB or sham operation (n=4-6, each group). We examined the effect of NF-κB inhibitor, pyrrolydine-dithiocarbamate (PDTC: 200mg/kg/day, dietary, Day -1 to 28 for prevention, Day14 to 28 for treatment, n=4-6, each group) on RV function and inflammation.
Results: Comparing to sham, PAB of Day14 increased RV systolic pressure (78.6±5.2, vs. 31.1±3.3 mmHg, p<0.01), and end-diastolic pressure (RVEDP) (5.9±1.0 vs. 1.5±0.9 mmHg, p<0.01). PAB increased RVH, activation of p65 (NF-κB) (14.3±9.2 vs. 4.3±2.0μg/mg, p<0.05), infiltration of inflammatory cells, mainly CD68 positive macrophages (18.2±3.2 vs. 4.3±1.0cell/mm2, p<0.05), and fibrotic areas (Masson trichrome) (6.7±1.0 vs. 0.7±0.1%, P<0.01). Chronic administration of PDTC increased RVSP (vehicle: 70.0±2.7, prevention: 96.7±8.3, and treatment: 87.8±4.5mmHg, p<0.01) and decreased RVEDP (vehicle: 7.2±0.8, prevention: 3.8±0.4, and treatment: 3.8±1.3mmHg, p<0.01) indicating improvement of RV function. PDTC suppressed p65 activation, infiltration of CD68 positive macrophages, fibrosis (vehicle: 7.5±0.8, prevention: 2.4±0.4, and treatment: 3.2±0.5%, p<0.01) (Figure), and the mRNA levels of pro-inflammatory cytokines.
Conclusions: PAB activated NF-κB deteriorates RV function. The fact that PDTC reversed fibrosis and improved RV function indicates that the inhibition of NF-κB would be a novel therapeutic target for RV dysfunction in PAH
Author Disclosures: K. Yoshida: None. K. Abe: None. K. Saku: None. K. Sunagawa: None.
- © 2016 by American Heart Association, Inc.