scholarly journals Mechanisms underlying the relaxation by A484954, a eukaryotic elongation factor 2 kinase inhibitor, in rat isolated mesenteric artery

2018 ◽  
Vol 137 (1) ◽  
pp. 86-92 ◽  
Author(s):  
Tomoko Kodama ◽  
Muneyoshi Okada ◽  
Hideyuki Yamawaki
Keyword(s):  
Mesenteric Artery ◽  
Kinase Inhibitor ◽  
Elongation Factor ◽  
Elongation Factor 2 ◽  
Eukaryotic Elongation Factor 2 ◽  
Eukaryotic Elongation Factor

Abstract 171: Eukaryotic Elongation Factor 2 Kinase (eEF2K) Mediates Vascular Inflammation and Development of Hypertension in Spontaneously Hypertensive Rats

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Tatsuya Usui ◽  
Muneyoshi Okada ◽  
Yukio Hara ◽  
Hideyuki Yamawaki
Keyword(s):  
Mesenteric Artery ◽  
Inflammatory Responses ◽  
Vascular Inflammation ◽  
Elongation Factor ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
Elongation Factor 2 ◽  
Eukaryotic Elongation Factor 2 ◽  
Eukaryotic Elongation Factor ◽  
Tnf Α

Eukaryotic elongation factor 2 kinase (eEF2K) is a Ca 2+ /calmodulin-dependent protein kinase that mainly regulates protein translation. We have recently demonstrated that eEF2K protein increases in mesenteric artery from spontaneously hypertensive rats (SHR) compared with Wistar Kyoto rats. Pathogenesis of hypertension is modulated in part by vascular inflammation. We examined whether eEF2K mediates vascular inflammatory responses and development of hypertension. In human umbilical vein endothelial cells (HUVECs) and rat mesenteric arterial smooth muscle cells (SMCs), eEF2K phosphorylation was increased by TNF-α (48% increase in HUVECs and 46% increase in SMCs, n=5, P<0.01). In HUVECs, small interfering RNA (siRNA) against eEF2K inhibited induction of VCAM-1 (62% inhibition, n=4) and e-selectin (29% inhibition, n=6) as well as monocyte adhesion (43% inhibition, n=4) by TNF-α (P<0.01). eEF2K siRNA inhibited phosphorylation of JNK (76% inhibition) and NF-κB (54% inhibition) as well as reactive oxygen species (ROS) production (69% inhibition) by TNF-α (n=4, P<0.01). In SMCs, eEF2K siRNA inhibited VCAM-1 induction (41% inhibition, n=5, P<0.05) and phosphorylation of JNK (65% inhibition, n=6, P<0.01) and NF-κB (83% inhibition, n=4, P<0.05) by TNF-α. In vivo, increased blood pressure (systolic blood pressure, SHR; 199.5 mmHg vs. SHR+NH125; 159.4 mmHg, n=4, P<0.01) and increased eEF2K phosphorylation (68% inhibition, n=4), induction of VCAM-1 (62% inhibition, n=4, P<0.05) and hypertrophy (70% inhibition, n=4) in SHR mesenteric artery was normalized by long-term treatment with NH125 (500 μg/kg/day for 6 weeks). In SHR mesenteric artery, impairment of acetylcholine (ACh)-induced endothelium-dependent relaxation was normalized by NH125 (relaxation induced by 30 nM ACh, SHR; 60.4% vs. SHR+NH125; 90.0%, n=4, P<0.01). The present results for the first time demonstrated in cultured ECs and SMCs that eEF2K mediates TNF-induced inflammatory responses via ROS-dependent mechanism. It is also suggested that eEF2K may mediate development of hypertension in SHR likely via inflammation, hypertrophy and endothelial dysfunction.

scholarly journals Eukaryotic elongation factor 2 kinase regulates the development of hypertension through oxidative stress-dependent vascular inflammation

2013 ◽  
Vol 305 (5) ◽  
pp. H756-H768 ◽  
Author(s):  
Tatsuya Usui ◽  
Muneyoshi Okada ◽  
Yukio Hara ◽  
Hideyuki Yamawaki
Keyword(s):  
Superior Mesenteric Artery ◽  
Mesenteric Artery ◽  
Vascular Inflammation ◽  
Elongation Factor ◽  
Ros Production ◽  
Elongation Factor 2 ◽  
Eukaryotic Elongation Factor 2 ◽  
Eukaryotic Elongation Factor ◽  
Tnf Α ◽  
Stress Dependent

Eukaryotic elongation factor 2 kinase (eEF2K) is a Ca2+/calmodulin-dependent protein kinase. We recently demonstrated that eEF2K protein increases in mesenteric artery from spontaneously hypertensive rats (SHR). Pathogenesis of hypertension is regulated in part by vascular inflammation. We tested the hypothesis whether eEF2K mediates vascular inflammatory responses and development of hypertension. In vascular endothelial cells, small interfering RNA (siRNA) against eEF2K inhibited induction of VCAM-1 and endothelial-selectin as well as monocyte adhesion by TNF-α (10 ng/ml). eEF2K siRNA inhibited phosphorylation of JNK and NF-κB p65 as well as reactive oxygen species (ROS) production by TNF-α. In vascular smooth muscle cells, eEF2K siRNA also inhibited VCAM-1 induction and phosphorylation of JNK and NF-κB by TNF-α. In vivo, increased blood pressure in SHR and ROS production, induction of inflammatory molecules, and hypertrophy in SHR superior mesenteric artery were reduced by an eEF2K inhibitor NH125 (500 μg·kg−1·day−1). In SHR superior mesenteric artery, impairment of ACh-induced relaxation was normalized by NH125. The present results for the first time demonstrate that eEF2K mediates TNF-α-induced vascular inflammation via ROS-dependent mechanism, which is at least partly responsible for the development of hypertension in SHR.

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