Abstract 758: Sustained Pulmonary Hypertension and Pulmonary Vascular Inflammation in BMPR2+/− Mice Overexpressing 5-Lipoxygenase and Treated with Monocrotaline
Familial idiopathic pulmonary arterial hypertension (PAH) is associated with germline mutations in bone morphogenetic protein receptor type II (BMPR2). Yet, disease expression occurs in not more that 20% of individuals with BMPR2 mutations, suggesting a requirement for either an environmental stimulus or the presence of a disease-modifying gene. Inflammation is believed to be an important determinant of PAH. For this reason, we studied the effect of 5-lipoxygenase (5LO) overexpression and monocrotaline (MCT) on the development of pulmonary hypertension in BMPR2+/− mice. At 3 weeks after treatment, BMPR2+/− mice overexpressing 5LO and treated with MCT (B5LM) had a significant increase in right ventricular systolic pressure compared with wildtype mice overexpressing 5LO and treated with MCT (W5LM) (23 ± 5 vs. 15± 2 mmHg, p<0.05), as well as a significant decrease in cardiac output (6.0 ± 0.6 vs. 2.9 ± 0.7 ml/min, p<0.01) and an estimated doubling of pulmonary vascular resistance. This increase in right-sided pressure was accompanied by a dramatic increase in the number of fully muscularized pulmonary arterioles in B5LM compared with W5LM (26 ± 5 vs. 7 ± 1 muscularized distal vessels/20 fields, p<0.05), and a significant increase in perivascular CD45+ cells in B5LM compared with W5LM (243 ± 10 vs. 173 ± 20 cells/10 fields), which were principally T-lymphocytes and macrophages. Quantitative real-time RT-PCR analysis of lung tissue showed that mRNA for MIP-alpha and Fractalkin receptor were significantly increased in B5LM compared with W5LM (p<0.05). These data show that the combination of 5LO overexpression and MCT leads to the development of PAH in BMPR2+/− mice via a mechanism that involves chemokine activation and perivascular leukocyte recruitment. These results suggest that inflammation promotes pulmonary hypertension in a BMPR2+/− background, and give insight into the complex determinants of the PAH phenotype.