title: Eukaryotic elongation factor 2 kinase mediates monocrotaline-induced pulmonary arterial hypertension via reactive oxygen species-dependent vascular remodeling.
abstract: 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 oxidase-1 expression and ROS generation as well as matrix metalloproteinase-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.
authors.affiliation: Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Towada, Aomori, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kameshima
authors.affiliation: Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Towada, Aomori, Japan.
authors.forename: Kyosuke
authors.initials: K
authors.lastname: Kazama
authors.affiliation: Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Towada, Aomori, Japan.
authors.forename: Muneyoshi
authors.initials: M
authors.lastname: Okada
authors.affiliation: Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Towada, Aomori, Japan yamawaki@vmas.kitasato-u.ac.jp.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Yamawaki
mesh_terms: D000818:Animals; D054736:Elongation Factor 2 Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D016686:Monocrotaline / Q000633:toxicity; D009247:NADH, NADPH Oxidoreductases / Q000235:genetics / Q000378:metabolism; D000074624:NADPH Oxidase 1; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*; D066253:Vascular Remodeling
chemical_list: C000599753:A-484954; D011725:Pyridines; D011743:Pyrimidines; D017382:Reactive Oxygen Species; D016686:Monocrotaline; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; C517691:Eef2k protein, rat; D054736:Elongation Factor 2 Kinase; D020778:Matrix Metalloproteinase 2; C522363:Mmp2 protein, rat
keywords: eukaryotic elongation factor 2 kinase; matrix metalloproteinase; pulmonary hypertension; reactive oxygen species; vascular remodeling