Abstract 16372: Effect of T-Cell Activity on Susceptibility of Mice for Development of Severe Pulmonary Arterial Hypertension in Response to SU5416 and Chronic Hypoxia
Introduction: Lung endothelial cell (EC) injury and apoptosis is believed to contribute to pulmonary arterial hypertension (PAH) by triggering reactive vascular inflammation and cell proliferation, leading to obliteration of distal lung arterioles. SU5416 (SU) induces lung EC apoptosis, and combined with chronic hypoxia (CH) leads to severe PAH in rats. Moreover, athymic rats, lacking mature T-cells including T-regulatory (T-reg) cells, exhibit increased susceptibility to severe PAH in response to SU, even in the absence of CH. In contrast, mice are resistant to severe PAH induced by SU/CH. Hypothesis: The higher levels of T-reg cell activity compared to rats contributes to the lack of a severe PAH phenotype in mice in response to SU/CH, and this can be overcome by using an immunodeficient, athymic strain and/or by multiple dosing.
Methods: Wild type or athymic (B6.Cg-Foxn1nu/J) C57Bl6/J mice were exposed to normoxia or 3 weeks of CH (9-10% O2), combined with a single or multiple (3-6) weekly or biweekly injections of 20mg/kg SU. Sprague-Dawley rats were treated with a single dose of SU and 3 weeks of CH. Assessments were performed at 3 weeks.
Results: Administration of SU/CH to WT mice (1, 3 or 6 SU injections) failed to increase RVSP compared to CH alone (43.1±1.2, 40.1±2.5, & 32.7±1.2, respectively vs. 38.2±2.3 CH; n=5-9/group) or RV remodeling(0.4±0.01, 0.39±0.02, 0.45±0.03, respectively vs. 38.2±2.3 CH; n=5 10/group). Moreover, treatment of athymic mice with up to 3 doses of SU/CH did not worsen PAH phenotype compared to CH alone (RVSP: 31.1±2 vs. 29.9±1.0, respectively; n=3) or RV remodeling (0.39±0.01 vs. 0.42±0.01, respectively; n=3). In contrast, rats given a single injection of SU/CH exhibited a marked exaggeration of PAH compared with CH alone (RVSP 80.0±8.2 vs. 40±2mmHg, respectively) and RV hypertrophy (0.56±0.03 and 0.33±0.1, respectively, all p< 0.001). Finally, no occlusive arterial remodeling was seen in treated WT or athymic mice; whereas, typical obliterative lesions were seen in the rat model.
Conclusion: These findings suggest that mechanisms other than differences in T-reg cell activity account for the marked difference in lung vascular response to EC apoptosis between mice and rats, and that this cannot be overcome by increasing the SU dose
- © 2012 by American Heart Association, Inc.