Extracellular Signal-Regulated Kinase (ERK1/2) Contributes to Endotoxin-Induced Hyporeactivity via Nitric Oxide and Prostacyclin Production in Rat Aorta

Abstract

This study was conducted to determine if mitogen-activated protein kinases (MAPKs) such as extracellular signal-regulated kinase (ERK1/2) contribute to endotoxin-induced vascular hyporeactivity via nitric oxide (NO) and/or prostacyclin (PGI₂) production in the rat isolated thoracic aorta. Incubation of endothelium-intact rings with endotoxin (100 µg/ml) for 4 h decreased the E_max value and increased the EC₅₀ value of norepinephrine. The endotoxin-induced increase in the EC₅₀ value of norepinephrine was decreased by phenylene-1,3-bis[ethane-2-isothiourea] dihydrobromide (1,3-PBIT), a selective inducible NO synthase inhibitor, and U0126, a selective inhibitor of ERK1/2 phosphorylation by MAPK kinase. The endotoxin-induced decrease in the E_max value of norepinephrine was reversed by 1,3-PBIT and further decreased by U0126. 1,3-PBIT and U0126 decreased the endotoxin-induced increase in the tissue nitrite and 6-keto-PGF₁_α levels. These data suggest that events related to the activation of ERK1/2 contribute to the endotoxin-induced hyporeactivity by increasing NO and PGI₂ production.

5,14-HEDGE, a 20-HETE mimetic, reverses hypotension and improves survival in a rodent model of septic shock: Contribution of soluble epoxide hydrolase, CYP2C23, MEK1/ERK1/2/IKKβ/IκB-α/NF-κB pathway, and proinflammatory cytokine formation

“…In addition, LPS-induced increase in ERK1/2 activity, but not phosphorylated MEK1, IκB-α, and NF-κB levels, was reversed by 20-HEDE in the renal tissue. These observations together with previous studies [37,39–46,53–57] suggest that increased production of EETs as well as decreased expression and/or activities of sEH and MEK1/ERK1/2/IKKβ/IκB-α/NF-κB pathway participates in the effect of 5,14-HEDGE to prevent the LPS-induced inflammatory response associated with a decrease in MAP and rise in HR in endotoxemic rats and mortality in mice. In addition, it seems that transcriptional (e.g., gene expression), translational (e.g., mRNA expression and stability), and posttranslational mechanisms (e.g., protein expression and stability) as well as changes in enzyme activity are involved in the regulation of sEH and CYP2C23 expression by 5,14-HEDGE in the rodent model of septic shock.…”

“…These observations suggest that MEK1/ERK1/2 pathway involves in the vascular hyporeactivity to vasoconstrictor agents and decreased blood pressure in endotoxemic rats. Indeed, as shown by our group previously, a selective inhibitor of phosphorylation of ERK1/2 by MEK1, 1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadien (U0126) prevented the endotoxin-induced fall in MAP and increase in HR in vivo as well as vascular hyporeactivity to norepinephrine associated with increased phosphorylation of ERK1/2 in vitro [53] and ex vivo [54,55]. These findings suggest that MEK1/ERK1/2 pathway-induced inhibition of the formation of vasoconstrictor mediators, such as 20-HETE, and removal of its influence on vascular tone may contribute to the hypotension, tachycardia, and vascular hyporeactivity in endotoxic shock.…”

Vitamin E supplementation reverses renal altered vascular reactivity in chronic bile duct-ligated rats

“…But also a NO overproduction might be driven by oxidant stress via a phosphoinositide 3-kinase/Akt and MAPK/extracellular signal-regulated kinase/ ERK1/2 pathways (12,43), which have been implicated in the endotoxin-induced vascular hyporeactivity (30) where NO and free radicals are greatly elevated. Then, during cirrhosis, the resulting disequilibrium between the unrestrained oxidative stress and NO, and their interactions, favor the activation of ERK1/2.…”

“…Thus, superoxide anion (O 2 Ϫ ) can quickly react with nitric oxide (NO), further producing new oxidative-derived substances such as peroxynitrite (7), which can potentially modify the vascular function (8,11,48). But they can also regulate intracellular signaling molecules, such as the extracellular regulated kinase 1/2 (ERK1/2), which is implicated in contractile functions of vascular cells under physiological (22,28) and pathological conditions (26,30,44,47), although its role remained unclear under liver cirrhosis. Therefore, we hypothesized that during biliary cirrhosis, oxidative stress contributes to the systemic and renal excretory disturbances by altering vascular reactivity in the systemic and renal circulations.…”

A 20-Hydroxyeicosatetraenoic Acid Agonist, N-[20-Hydroxyeicosa-5(z),14(z)-Dienoyl]glycine, Opposes the Fall in Blood Pressure and Vascular Reactivity in Endotoxin-Treated Rats

“…At the end of the experiment, the rats were killed, and the thoracic aortas and superior mesenteric arteries were isolated as previously described (11, 12). The vessels were cleared of adventitial tissue and cut into rings of 2 to 3 mm in length.…”