Abstract 15221: Pulmonary Artery Banding Induces NF-κB activated Inflammation and Deteriorates RV Function

Abstract

Background: Right ventricular (RV) dysfunction contributes to poor prognosis in patients with pulmonary hypertension. Although pulmonary artery banding (PAB) induces RV inflammation, its mechanisms are poorly understood. Hypothesis: We assessed the hypothesis that RV pressure overload induced by PAB leads to RV dysfunction through NF-κB-mediated inflammation and fibrosis. Methods and Results: We banded the main PA using an 18-gauge needle in adult Sprague-Dawley rats (BW: 180-220g). We measured hemodynamics and analyzed immunohistochemistry of RV at Day 1, 3, 7 and 14 after PAB (n=4-6, each group). PAB time-dependently increased RV systolic pressure (sham: 31.1±5.7 vs. Day14: 73.2±11.8mmHg, p<0.01), RV end-diastolic pressure (RVEDP) (sham: 1.5±0.9 vs. Day14: 5.8±2.1mmHg, p<0.05) and RV hypertrophy (ratio of RV/LV+septum weight) (sham: 0.29±0.04 vs. Day14: 0.68±0.08, p<0.01) with high expression of activated p65 (NF-κB). PAB increased inflammatory cells, mainly CD68 positive macrophages (sham: 5.6±1.6 vs. Day1: 46.4±9.7 cell/mm2, p<0.01), and fibrosis areas (Masson trichrome staining) time-dependently (sham: 0.7±0.2 vs. Day14: 7.6±0.8%, p<0.01). Chronic administration of NF-κB inhibitor, pyrrolydine-dithiocarbamate (PDTC, 200mg/kg/day, orally, from Day 0 to 28), in PAB rats (n=4-7, each group) markedly decreased RVEDP (vehicle: 9.0±0.7 vs. PDTC: 3.4±1.3mmHg, p<0.01), attenuated the expression of activated p65 and infiltration of CD68 positive macrophages (vehicle: 24.1±10.4 vs. PDTC: 5.6±2.0 cell/mm2, p<0.01), and reduced fibrosis (vehicle: 8.7±1.1 vs. PDCT: 2.4±0.8%, p<0.01) (Figure). Conclusions: These findings indicate that PAB immediately activates NF-κB and increases macrophage infiltration. Second, chronic treatment with PDTC attenuates NF-κB activation and macrophage infiltration in RV, leading to reduced fibrosis as well as RVEDP. NF-κB inhibition may be a therapeutic target for the RV dysfunction.