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Background: Pulmonary arterial hypertension (PAH) is a progressive angioproliferative disease with high morbidity and mortality. Although the histopathology is well described, its pathogenesis is largely unknown. We previously identified the increased presence of mast cells and their markers in a rat model of flow-associated PAH. The aim of this study was to test the effect of mast cell stabilization on pulmonary vascular remodeling in experimental PAH.Methods: Rats with flow-associated PAR created by monocrotaline and an aorto-caval shunt were treated with the mast cell stabilizer cromolyn and compared with untreated rats and control rats. Further, we treated a group of rats with PAR with an inhibitor (TY-51469) of chymase, one of the mast cell proteases. The effects on pulmonary vascular remodeling and hemodynamics were assessed.Results: Rats with PAR had increased mast cells, chymase activity, and inflammatory markers. Treatment with mast cell stabilizer attenuated pulmonary vascular remodeling but not hemodynamics. A lower pulmonary chymase activity correlated with more favorable pulmonary vascular remodeling as well as hemodynamics and inflammatory markers.Conclusions: We showed in rats with PAH that mast cell stabilization attenuated pulmonary vascular remodeling and that a lower chymase activity correlated with more favorable hemodynamics and pulmonary vascular remodeling. The results of this experimental study support the concept of the use of antiinflammatory therapy by mast cell stabilizers, a group of drugs already licensed for clinical use, to attenuate disease progression in PAH. CHEST 2012; 141(3):651-660

Aims Right ventricular (RV) dysfunction is a major determinant of long-term morbidity and mortality in congenital heart disease. The right ventricle (RV) is genetically different from the left ventricle (LV), but it is unknown as to whether this has consequences for the cellular responses to abnormal loading conditions. In the LV, calcineurin-activation is a major determinant of pathological hypertrophy and an important target for therapeutic strategies. We studied the functional and molecular adaptation of the RV in mouse models of pressure and volume load, focusing on calcineurin-activation. Methods and results Mice were subjected to pulmonary artery banding (PAB), aorto-caval shunt (Shunt), or sham surgery (Control). Four weeks later, mice were functionally evaluated with cardiac magnetic resonance imaging, pressure measurements, and voluntary cage wheel exercise. Right ventricular hypertrophy and calcineurin-activation were assessed after sacrifice. Mice with increased pressure load (PAB) or volume load (Shunt) of the RV developed similar degrees of hypertrophy, yet revealed different functional and molecular adaptation. Pulmonary artery banding increased expression of Modulatory-Calcineurin-Interacting-Protein 1 (MCIP1), indicating calcineurin-activation, and the ratio of beta/alpha-Myosin Heavy Chain (MHC). In addition, PAB reduced exercise capacity and induced moderate RV dilatation with normal RV output at rest. In contrast, Shunt did not increase MCIP1 expression, and only moderately increased beta/alpha-MHC ratio. Shunt did not affect exercise capacity, but increased RV volumes and output at rest. Conclusions Pressure and volume load induced different functional and molecular adaptations in the RV. These results may have important consequences for therapeutic strategies to prevent RV failure in the growing population of adults with congenital heart disease.

In flow-associated pulmonary arterial hypertension (PAH), increased pulmonary blood flow is an essential trigger for neointimal formation. Using microarray analysis, we recently found that the early growth response protein 1 (Egr-1) transcription factor is increased in experimental flow-associated end-stage PAH. Its role in PAH development is unknown. Here, we assessed the spatiotemporal expression of Egr-1 during neointimal development in flow-associated PAH. Flow-associated PAH was produced in rats by combining monocrotaline administration with an aortocaval shunt. Animals were sacrificed 1 day before or 1 day, 1 week, or 4 to 5 weeks after flow addition. Egr-1 expression was spatiotemporally assessed using laser microdissection, quantitative real-time PCR and immunohistochemistry. In addition, Egr-1 expression was assessed in a non-neointimal pulmonary hypertension model and in human PAH associated with congenital shunt. In 4 to 5 weeks, rats subjected to increased flow developed PAH with neointimal lesions. Egr-1 mRNA was increased 1 day after flow addition and in end-stage PM!, whereas monocrotaline only did not result in increased Egr-1 mRNA. Directly after flow addition, Egr-1 was expressed in endothelial cells. During disease development, Egr-1 protein expression increased and migrated throughout the vessel wall. In PM! patients, Egr-1 was expressed in vessels with media hypertrophy and neointimal lesions, including plexiform lesions. Thus, Egr-1 may be an important regulator in the development of pulmonary neointimal lesions induced by increased pulmonary blood flow. (Am J Pathol 2011, 179:2199-2209; DOI: 10.1016/j.ajpath.2011.07.030)