Contribution of iNOS/sGC/PKG pathway, COX-2, CYP4A1, and gp91phox to the protective effect of 5,14-HEDGE, a 20-HETE mimetic, against vasodilation, hypotension, tachycardia, and inflammation in a rat model of septic shock

Tunçtan, Bahar; Korkmaz, Belma; Sarı, Ayşe Nihal; Kacan, Meltem; Ünsal, Demet; Serin, Mehmet Sami; Buharalioğlu, C. Kemal; Şahan-Fırat, Seyhan; Cuez, Tuba; Schunck, Wolf Hagen; Manthati, Vijaya L.; Falck, John R.; Malik, Kafait U.

doi:10.1016/j.niox.2013.05.001

Cited by 57 publications

(60 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The study by Dordea et al (5a) therefore adds a further piece to this puzzle illustrating that loss of NO-sGC signaling uncovers this hypertensive pathway. These findings also marry with a recent report that excessive sGC signaling triggered by inducible NO synthase-derived NO suppresses 20-HETE formation (albeit via downregulation of Cyp4A1) in the context of sepsis; in this setting, promoting the vasoconstrictor activity of 20-HETE actually reverses the associated hypotension and might have beneficial activity (18). The mechanisms underlying these reciprocal interactions between NO, sGC, and 20-HETE may well exist at more than one level.…”

supporting

confidence: 81%

Guanylyl cyclase can't stand the HETE

Hobbs

2016

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

NITRIC OXIDE (NO)-sensitive isoforms of heterodimeric guanylyl cyclase [␣ 1 ␤ 1 -and ␣ 2 ␤ 1 -soluble guanylyl cyclases (sGC)], extend an umbrella of protection throughout the cardiovascular system, with wide-ranging effects on local blood flow, platelet and leukocyte reactivity, vessel morphology, and cardiac structure and function (5, 10). Consequently, dysfunctional sGC signaling precipitates cardiovascular disease in an analogous manner to deficits in NO bioactivity, perhaps illustrated most tangibly in the context of human pathophysiology by genomewide association studies (GWAS) identifying mutations in the GUCY1A3 and GUCY1B3 genes, which encode the two principal subunits of the enzyme (sGC␣ 1 and sGC␤ 1 , respectively), to associate with a hypertensive phenotype (6). Preclinical models have also borne out a clear relationship between sGC activity, local vascular tone, and systemic blood pressure. This is best illustrated by the hypertensive phenotype in mice with genetic deletions of either sGC␣ 1 or sGC␤ 1 (3,8,9,17,19). Interestingly, the sGC␣ 1 and sGC␤ 1 null mice exhibit a strainand sex-specific rise in blood pressure (3,17), and this phenomenon has shed light on mechanisms critical to the vasoprotective functions of NO-sGC signaling, both in terms of endothelium-dependent dilatation and more global effects on neurohormonal axes. For example, the sex difference in response to sGC deletion dovetails well with studies revealing a marked increase in blood pressure in male endothelial NO synthase (eNOS)/cyclooxygenase-1 double knockout (KO) mice, which are unable to synthesize two principal endotheliumderived vasodilators, NO and prostacyclin (14). In these animals, endothelium-dependent relaxation is restricted to that provided by hyperpolarization pathways, i.e., endotheliumdependent hyperpolarization (EDH), which are upregulated by female sex steroids (20); in contrast, the predominant endothelium-derived dilator in males is NO, thereby explaining why deletion of eNOS or sGC results in raised blood pressure. Consequently, sGC KO mice are good models with which to ascertain the role of male sex steroids, primarily testosterone, in the development of hypertension. For example, previous studies capitalizing on the sGC␣ 1 KO mice have revealed an androgen-driven increase in renin activity that contributes to the hypertensive phenotype in these animals (2, 3).In this issue of the American Journal of Physiology-Heart and Circulatory Physiology, Dordea et al. (5a) provide a timely and thought-provoking report identifying a further pathway upregulated by sGC␣ 1 deletion that underlies the development of hypertension in a sex-specific manner. Via linkage analysis, the authors identified a quantitative trait locus that associates with elevated blood pressure in male 129S6 mice that is shared by neither counterparts on a C57BL6 background nor female animals of either strain. In-depth analysis revealed that this region encodes a cluster of the cytochrome P-450 (Cyp) 4a isoforms, including Cyp4a10, Cyp4a12, and Cy...

show abstract

supporting

confidence: 81%

Guanylyl cyclase can't stand the HETE

Hobbs

2016

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

show abstract

“…Immunoblotting for MyD88, TAK1, phosphorylated TAK1, IκB-α, phosphorylated IκB-α, NF-κB p65, phosphorylated NF-κB p65, and actin proteins were performed according to the method described previously [42, 44, 45]. Briefly, tissue homogenates (75 μg of protein) were subjected to a 10% sodium dodecyl sulfate-polyacrylamide gel electrophoresis and then proteins were transferred to a nitrocellulose membrane.…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2014

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…This suggests that either PKG inhibited CYP4 activity or downregulated hypoxia-induced CYP4 expression. In this regards, NO is known to block CYP4-derived 20-HETE (1,62) and increased NO-mediated activity of cGMP/PKG has been associated with downregulation of CYP4A enzymes in various organs and renal arteries of a LPS-treated rat model of septic shock (60). The increase of PKG activity sumoylates Elk-1 and inactivates it (11).…”

Section: Discussionmentioning

confidence: 99%

20-HETE-induced mitochondrial superoxide production and inflammatory phenotype in vascular smooth muscle is prevented by glucose-6-phosphate dehydrogenase inhibition

Lakhkar

Dhagia

Joshi

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

. 20-HETE-induced mitochondrial superoxide production and inflammatory phenotype in vascular smooth muscle is prevented by glucose-6-phosphate dehydrogenase inhibition. Am J Physiol Heart Circ Physiol 310: H1107-H1117, 2016. First published February 26, 2016 doi:10.1152/ajpheart.00961.2015 produced by cytochrome P-450 monooxygenases in NA-DPH-dependent manner is proinflammatory, and it contributes to the pathogenesis of systemic and pulmonary hypertension. In this study, we tested the hypothesis that inhibition of glucose-6-phosphate dehydrogenase (G6PD), a major source of NADPH in the cell, prevents 20-HETE synthesis and 20-HETE-induced proinflammatory signaling that promotes secretory phenotype of vascular smooth muscle cells. Lipidomic analysis indicated that G6PD inhibition and knockdown decreased 20-HETE levels in pulmonary arteries as well as 20-HETEinduced 1) mitochondrial superoxide production, 2) activation of mitogen-activated protein kinase 1 and 3, 3) phosphorylation of ETS domain-containing protein Elk-1 that activate transcription of tumor necrosis factor-␣ gene (Tnfa), and 4) expression of tumor necrosis factor-␣ (TNF-␣). Moreover, inhibition of G6PD increased protein kinase G1␣ activity, which, at least partially, mitigated superoxide production and Elk-1 and TNF-␣ expression. Additionally, we report here for the first time that 20-HETE repressed miR-143, which suppresses Elk-1 expression, and miR-133a, which is known to suppress synthetic/secretory phenotype of vascular smooth muscle cells. In summary, our findings indicate that 20-HETE elicited mitochondrial superoxide production and promoted secretory phenotype of vascular smooth muscle cells by activating MAPK1-Elk-1, all of which are blocked by inhibition of G6PD.20-HETE; TNF-␣; elk-1; mitogen-activated protein kinase 1 and 3; extracellular signal regulated kinase 2 and 1; protein kinase G; miRs 20-HYDROXYEICOSATETRAEONIC acid (20-HETE), the -hydroxylation metabolite of arachidonic acid (AA), is produced by cytochrome P-450 monooxygenases of the (CYP4A and CYP4F gene) families in an NADPH-dependent manner (49). 20-HETE is proinflammatory and it regulates vascular and renal function (49). It also plays a critical role in the pathogenesis of systemic hypertension, renal stenosis, and atherosclerosis (27,63,65). 20-HETE increased by hypoxia inhibits hypoxia-induced pulmonary artery constriction (69). However, its role in the hypoxia-induced inflammation of pulmonary arteries or lungs is yet unclear. NEWS & NOTEWORTHY 20-Hydroxyeicosatetraeonic acid (20-HETE) plays a criticalRecently, our laboratory also found that 20-HETE is involved in promoting prolonged hypoxia-induced pulmonary vasoconstriction and that glucose-6-phosphate dehydrogenase (G6PD), which is a major producer of NADPH in the cell, and cytochrome P-450 monooxygenase enzymes are functionally coupled in vascular smooth muscle tissue (unpublished observations). G6PD inhibition relaxes pulmonary arteries by decreasing intracellular calcium (20), prevents switching of vascular smooth ...

show abstract

Contribution of iNOS/sGC/PKG pathway, COX-2, CYP4A1, and gp91phox to the protective effect of 5,14-HEDGE, a 20-HETE mimetic, against vasodilation, hypotension, tachycardia, and inflammation in a rat model of septic shock

Cited by 57 publications

References 57 publications

Guanylyl cyclase can't stand the HETE

Guanylyl cyclase can't stand the HETE

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

20-HETE-induced mitochondrial superoxide production and inflammatory phenotype in vascular smooth muscle is prevented by glucose-6-phosphate dehydrogenase inhibition

Contact Info

Product

Resources

About