Abstract
Introduction. The p38 mitogen-activated protein kinases (MAPK) considered as a key signaling pathway that responds to varied stresses, including those that contribute to heart failure. However, the role of p38 MAPK in pulmonary vascular and right ventricular remodeling is still to be elucidated. Therefore we thought to investigate the effects of p38alfa MAPK inhibition on pressure overload induced RV remodeling.
Methods. We have investigated the effects of p38 MAPK inhibitor PHA-00797804 (Pfizer, USA) in mice subjected either to hypoxia-induced PH or to pulmonary artery banding (PAB). After 21 days, mice exposed to hypoxia were randomized and treated by vehicle or 5 mg/kg bw PHA-00797804 for 14 days. PAB mice were treated by vehicle or PHA-00797804 in a dose 5 mg/kg bw from day 7 to 21. RV function and remodeling determined using echocardiography, invasive hemodynamic measurement and hitomorphometry.
Results. The 38 MAPK inhibition significantly decreased pulmonary vascular remodeling and markedly improved RV functions in hypoxic mice. Additionally, PHA-00797804 significantly increased cardiac output, tricuspid annular plane systolic excursion and improved myocardial performance index in PAB mice compared with placebo treated animals. Moreover, improvement in RV functions was associated with strong antifibrotic effect of PHA-00797804.
Conclusion. We have demonstrated that p38 MAPK plays a significant role in pulmonary vascular and RV remodeling. Inhibition of p38 MAPK by PHA-00797804 effectively improved RV remodeling and function in experimental models of PAH and RV hypertrophy.
- © 2014 ERS