Pulmonary Hypertension (PH), a fatal cardio-pulmonary disease, is characterized by pulmonary vascular remodeling, due to excessive proliferation of pulmonary vascular cells, and increased right ventricle pressure. Although, a number of pathways are involved in pathophysiology of PH, there are increasing evidences which suggest an important role for inflammation in PH. Mitogen-Activated Protein Kinase (MAPK)-Activated Protein Kinase 2 (MK2), a major downstream target of p38 MAPK, plays a pivotal role in inflammation. Therefore, we hypothesized that MK2 may contribute in pathophysiology of PH. For this, Human Pulmonary Artery Smooth Muscle Cells (HPASMCs) were exposed to hypoxia for 72 h. HPASMCs proliferated extensively and significantly expressed MK2. siRNA mediated inhibition of MK2 significantly prevented the proliferation of HPASMCs, reduced expression of MK2 and decreased inflammatory markers (IL-1β and NF-ĸb). Further, we confirmed the role of MK2 in PH by using MK2-deficient mice (MK2-/-). Monocrotalin (MCT) (600 mg/kg, i.p.) was administered once a week for 5 weeks in wild type and MK2-/- mice. As compared to control mice, there was a significant rise in right ventricle pressure (RVP) in wild type mice but no significant rise in RVP was observed in MK2-/- mice. MCT-treated mice (wild type) also showed increased RV mass and reduction in ejection fraction as compared control mice whereas MCT treated MK2-/- mice showed no significant increase in RV mass and reduction in ejection fraction. Further, pharmacological inhibition of MK2 by MMI-0100 in MCT treated PH rats reduced right ventricle pressure, hypertrophy, right ventricle mass and improved ejection fractions and other cardiac functions. These results show that MK2 plays an important role in increasing inflammation and its inhibition may be protective in pulmonary hypertension.