Inhibition of Mitogen-Activated Protein Kinase (MAPK)-Activated Protein Kinase 2 (MK2) is Protective in Pulmonary Hypertension

Abstract

Mitogen-Activated Protein Kinase (MAPK)-Activated Protein Kinase 2 (MK2), downstream to p38MAPK (p38mitogen-activated protein kinase), regulates cellular inflammation and proliferation. So far, the role of MK2 has been studied in many cardiovascular diseases, but it remains unexplored in pulmonary hypertension (PH). Therefore, to investigate the role of MK2 in the PH pathogenesis, human pulmonary artery smooth muscle cells were exposed to hypoxia (1% O 2 ) for 72 hours, and MK2 was inhibited by siRNA. We observed significantly increased MK2 expression, inflammatory cytokines, proliferation, mitochondrial dysfunction, and apoptosis resistance in hypoxic human pulmonary artery smooth muscle cells, which were reversed by treatment with MK2 siRNA. For in vivo studies, male Sprague Dawley rats were treated with monocrotaline (60 mg/kg, SC, once) to induce PH. To inhibit MK2, a peptide MMI-0100 (40 μg/kg, IP daily, 5 weeks for preventive and 3 weeks for curative study) was administered. MMI-0100 treatment decreased right ventricle pressure and hypertrophy, hallmarks of PH, in both preventive and curative study. MMI-0100-treated rats showed better cardiac functions as revealed by 2-dimensional echocardiography study. Furthermore, MMI-0100 reversed pulmonary vascular remodeling and improved pulmonary vascular relaxation in monocrotaline-treated rats. Finally, the above results were confirmed in MK2 knockout mice. MK2 knockout mice, received 600 mg/kg monocrotaline, subcutaneous weekly for 5 weeks, failed to develop PH and showed no increase in right ventricle pressure and hypertrophy. This study, therefore, proved that MK2 is involved in PH, and its inhibition may be a novel target for PH treatment.