Abstract 050: TLR4 Antagonism Prevents Early Left Ventricular Hypertrophy and Dysfunction Associated With Neonatal Hyperoxia Exposure

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Objective: Preterm birth is associated with proinflammatory conditions early in life. Our lab has shown in rats that transient neonatal exposure to high O 2 , an established model of prematurity-related conditions, leads to early CV inflammation and remodeling. TLR4 signaling is a critical link between inflammation and the pathogenesis of CVD. Whether programmed innate immune activation, via TLR4 signaling, impacts long term CVD is unknown. In our rat model of prematurity we investigated whether neonatal TLR4 antagonism will prevent the development of CV dysfunction. Methods: Male Sprague-Dawley pups were kept with their mother in 80% O 2 or room-air from day (P)3 to 10 of life. At P10, cardiac TLR4 protein expression was assessed. In other experiments, pups were treated i.p. with TLR4 antagonist LPSRS (100 μg/kg) or vehicle (0.9% NaCl) at P3, P6 and P9 (concomitant to O 2 exposure; n=6-9/group, max 3 animals/group/liter). At 4, 7 and 12 wks, body weights were measured and left ventricular (LV) echocardiography was performed under isoflurane using VEVO 3100 (VisualSonics). At 12 wks, central mean BP was measured under isoflurane by catheterism (BIOPAC, n=4-6). Comparisons were made using T-test or one-way ANOVA. Results: At P10, cardiac TLR4 protein expression was increased ~2 fold in O 2 -exposed pups compared to room-air controls (P<0.05). At 4 wks, body weight in vehicle- or LPSRS-treated O 2 -exposed animals (101±2 g and 106±2 g) was lower compared to room-air vehicles (117±2 g, P<0.01). Compared to room-air vehicles, vehicle- but not LPSRS-treated O 2 -exposed animals exhibited increased LV mass index (3.8±0.1 and 3.4±0.1 vs 3.3±0.1 mg/g, P<0.05 for O 2 -exposed vehicles vs controls), reduced ejection fraction (74±2 and 79±2 vs 82±1 %, P<0.05) and fractional shortening (43±2 and 48±2 vs 52±2 %, P<0.01), reduced cardiac output index (0.43±0.02 and 0.48±0.02 vs 0.56±0.03 ml/min/g, P<0.01), and decreased mitral E/A ratio (1.3±0.1 and 1.7±0.1 vs 1.7±0.1 mg/g, P<0.01). Findings were similar at 7 and 12 wks. At 12 wks, mean BP was higher in vehicle- but not LPSRS-treated O 2 -exposed animals, compared to controls (95±4 and 89±4 vs 81±4 mmHg, P<0.05). Conclusion: TLR4 antagonism prevents BP rise and LV hypertrophy and dysfunction associated to neonatal exposure to hyperoxia.