Eukaryotic elongation factor 2 kinase mediates monocrotaline-induced pulmonary arterial hypertension via reactive oxygen species-dependent vascular remodeling

摘要

Pulmonary arterial (PA) hypertension (PAH) is a progressive and lethal disease that is caused by increased vascular contractile reactivity and structural remodeling. These changes contribute to increasing pulmonary peripheral vascular resistance, finally leading to right heart failure and death. Eukaryotic elongation factor 2 kinase (eEF2K) is a Ca~(2+)/ calmodulin-dependent protein kinase. We previously revealed that eEF2K protein increases in the mesenteric artery from spontaneously hypertensive rats and partly mediates the development of hypertension via a promotion of ROS-dependent vascular inflammatory responses and proliferation and migration of vascular smooth muscle cells. However, a role of eEF2K in the pathogenesis of PAH is unknown. In the present study, we tested the hypothesis that eEF2K may be involved in the pathogenesis of PAH. PAH was induced by a single intraperitoneal injection of monocrotaline (MCT; 60 mg/kg) to rats. A specific eEF2K inhibitor, A-484954 (2.5 mg·kg~(-1)·day~(-1), was intraperitoneally injected for 14 days. Long-term A-484954 treatment inhibited MCT-induced increased PA pressure. It was revealed that A-484954 inhibited MCT-induced PA hypertrophy and fibrosis but not impairment of endothelium-dependent and -independent relaxation. Furthermore, A-484954 inhibited MCT-induced NADPH oxi-dase-1 expression and ROS generation as well as matrix metallopro-teinase-2 activation. In conclusion, the present results suggest that eEF2K at least partly mediates MCT-induced PAH via stimulation of vascular structural remodeling perhaps through NADPH oxidase-1/ ROS/matrix metalloproteinase-2 pathway.