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 need to be elucidated. Methods: The effects of p38 MAPK inhibitor PHA-00797804 (Pfizer, USA) investigated 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. The echocardiography, invasive hemodynamic measurement and hitomorphometry were performed. The myocardin-related transcription factor (MRTF) translocation and stress fibers formation were determined by immunofluorescence staining on isolated mouse cardiac fibroblasts. Results: The 38αMAPK inhibition significantly reversed pulmonary vascular remodeling and improved RV functions in hypoxia-induced PAH. However, to determine whether the effect in hypoxic mice was due to a direct impact of pharmacological interventions on RV or an indirect impact due to reduced pulmonary vascular resistance, we have investigated the effects of p38 MAPK inhibition in an established model of RVH and failure by PAB. The PHA-00797804 significantly increased cardiac output (p<0.001), tricuspid annular plane systolic excursion (p<0.001) and improved myocardial performance index (p<0.001) in PAB mice. Improvement in RV functions was associated with strong antifibrotic effect of PHA-00797804. The p38 MAPK inhibition reduced collagen synthesis and myofibroblast differentiation via MRTF A dependent mechanism. Conclusion: Inhibition of p38 MAPK improved RV remodeling and function in experimental models of RV hypertrophy and failure.
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