Effects of 5,14-HEDGE, a 20-HETE mimetic, on lipopolysaccharide-induced changes in MyD88/TAK1/IKKβ/IκB-α/NF-κB pathway and circulating miR-150, miR-223, and miR-297 levels in a rat model of septic shock

Abstract

Objectives We have previously demonstrated that a stable synthetic analog of 20-hydroxyeicosatetraenoic acid (20-HETE), N-(20-hydroxyeicosa-5[Z],14[Z]-dienoyl)glycine (5,14-HEDGE), which mimics the effects of endogenously produced 20-HETE, prevents vascular hyporeactivity, hypotension, tachycardia, inflammation, and mortality in a rodent model of septic shock. The present study was performed to determine whether decreased renal and cardiovascular expression and activity of myeloid differentiation factor 88 (MyD88)/transforming growth factor-activated kinase 1 (TAK1)/inhibitor of κB (IκB) kinase β (IKKβ)/IκB-α/nuclear factor-κB (NF-κB) pathway and reduced circulating microRNA (miR)-150, miR-223, and miR-297 expression levels participate in the protective effect of 5,14-HEDGE against hypotension, tachycardia, and inflammation in response to systemic administration of lipopolysaccharide (LPS). Methods Conscious male Wistar rats received saline (4 ml/kg) or LPS (10 mg/kg) at time 0. Blood pressure and heart rate were measured using a tail-cuff device. Separate groups of LPS-treated rats were given 5,14-HEDGE (30 mg/kg) 1 h after injection of saline or LPS. The rats were sacrificed 4 h after LPS challenge and blood, kidney, heart, thoracic aorta, and superior mesenteric artery were collected for measurement of the protein expression. Results LPS-induced fall in blood pressure and rise in heart rate were associated with increased MyD88 expression and phosphorylation of TAK1 and IκB-α in cytosolic fractions of the tissues. LPS also caused an increase in both unphosphorylated and phosphorylated NF-κB p65 proteins in the cytosolic and nuclear fractions as well as nuclear translocation of NF-κB p65. In addition, serum miR-150, miR-223, and miR-297 expression levels were increased in LPS-treated rats. These effects of LPS were prevented by 5,14-HEDGE. Conclusions These results suggest that downregulation of MyD88/TAK1/IKKβ/IκB-α/NF-κB pathway as well as decreased circulating miR-150, miR-223, and miR-297 expression levels participate in the protective effect of 5,14-HEDGE against hypotension, tachycardia, and inflammation in the rat model of septic shock.

Alteration in the expression of the renin-angiotensin system in the myocardium of mice conceived by in vitro fertilization†

“…In this study, miR-100, miR-297, and miR-758 were chosen as candidate genes after miRNA database prediction indicated that they interact with Col3a1, Agtr1a, and Col1a2, respectively. Previous studies have shown that plasma miR-100 is positively associated with coronary plaque vulnerability [72] can inhibit angiogenesis [73] and is involved in the development and growth of pancreatic cancer [74], while miR-297 is involved in septic shock [75]. In this study, the luciferase assay was used to demonstrate that miR-297 targets AGTR1 and promotes the proliferation of cardiomyocytes by regulating the expression of AGTR1 and CTGF.…”

Molecular mechanisms in differentiated thyroid cancer

“…Induction of sepsis with lipopolysaccharide (LPS) is associated with activation of MEK1/ERK1/2/IKKbeta/IKB-alpha/NF-KB and MyD88/TAK1/IKKbeta/IKB-alpha/NF-KB pathways that increases the levels of inflammatory cytokines (TNF-alpha and IL-8) (133, 228). These changes, along with the associated hypotension and tachycardia, can be prevented by administration of a stable 20-HETE mimetic, 5, 14-HEDGE.…”

“…This has been the subject of several recent and definitive reviews (11, 26, 117–121). The role of 20-HETE in ischemic and hemorrhagic stroke (122–125), acute renal failure (126, 127), toxemia of pregnancy (128), hepatorenal syndrome (129), vascular restenosis (23), angiogenesis (24), cardiac hypertrophy (130) and ischemia reperfusion (IR) injury (131), as well as shock (132, 133) is less well known and has received little attention in the literature. This review will focus on the emerging pathogenic role of 20-HETE as an important mediator in vascular dysfunction, inflammation in a variety of diseases.…”

Comprehensive Analysis of Serum microRNAs in Autoimmune Pancreatitis

“…Because the disease concept of AIP has become more widely understood among general clinicians, surgical resection of the pancreas for AIP is rarely performed in recent years. Previous studies have shown inflammation-related biological functions of miR-150 [30,31,32]. Lipopolysaccharide increased serum expression level of miR-150 in a rat model of septic shock [30].…”

“…Previous studies have shown inflammation-related biological functions of miR-150 [30,31,32]. Lipopolysaccharide increased serum expression level of miR-150 in a rat model of septic shock [30]. miR-150 is a component of a unique signaling network that controls the differentiation of cytotoxic T lymphocytes induced by IL-2 and inflammatory signals [31].…”