Endoplasmic Reticulum Ca2+ Release Modulates Endothelial Nitric-oxide Synthase via Extracellular Signal-regulated Kinase (ERK) 1/2-mediated Serine 635 Phosphorylation

Xiao, Zhihong; Wang, Tingting; Qin, Honghua; Huang, Chao; Feng, Yongzeng; Xia, Yong

doi:10.1074/jbc.m111.220236

Cited by 34 publications

(27 citation statements)

References 30 publications

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“…Our results show increased Akt phosphorylation at Ser 473 in the hearts of obese female rats, which further support the hypothesis that Akt regulates NFκB activity and thereby iNOS expression. Moreover, the role of ERK1/2 in iNOS activation has been demonstrated and increased ERK1/2 phosphorylation usually upregulates both NFκB activity and iNOS protein expression [46,49,[61][62][63]. However, in the present study there were no differences in ERK1/2 phosphorylation between obese and control female rats.…”

Section: Interestingly Mariappan Et Al Reported Increased Nfκb Exprcontrasting

confidence: 54%

Influence of a High-Fat Diet on Cardiac iNOS in Female Rats

Jovanović

Sudar-Milovanović

Obradović

et al. 2017

CVP

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Overexpression of inducible nitric oxide synthase (iNOS) is a key link between high-fat (HF) diet induced obesity and cardiovascular (CV) disease. Several studies have reported that oestradiol has cardioprotective effects that may be mediated through reduction of iNOS activity/expression. In the present study, female Wistar rats were fed a standard diet or a HF diet (balanced diet for laboratory rats enriched with 42% fat) for 10 weeks. Gene and protein expression of iNOS were measured in heart tissue. HF diet-fed rats exhibited a significant increase in cardiac iNOS mRNA by 695% (p<0.05), iNOS protein level by 248% (p<0.01), without changes in nitrate/nitrite levels. Expression of CD36 protein in plasma membranes was increased by 37% (p<0.05), while the concentration of free fatty acids (FFA) was reduced by 25% (p<0.01) in HF diet-fed rats. Expression of the p50 subunit of nuclear factor-κB (NFκB-p50) in heart lysate was increased by 77% (p<0.01) in HF diet-fed rats.Expression and phosphorylation of protein kinase B (Akt) and extracellular signal-regulated kinases 1/2 (ERK1/2) in control and HF diet-fed rats were also examined. Expression of Akt and ERK1/2 were unchanged between the groups. There was a significant increase in the ratio of phospho-Akt/total Akt but not for phospho-ERK1/2/total ERK1/2/ in HF-fed rats.Estrogen receptor-α levels (by 50%; p<0.05) and serum oestradiol concentrations (by 35%; p<0.05) were examined and shown to be significantly reduced in HF diet-fed rats. Our results revealed that a HF diet led to increased iNOS expression, most likely via a mechanism involving Akt and NFκB-p50 proteins. Decreased levels of oestradiol and ERα protein in the HF-fed group, in combination with increased iNOS levels are consistent with the hypothesis that oestradiol has a cardioprotective effect through its ability to regulate iNOS expression.Key words: cardioprotection, cardiovascular disease, oestradiol, inducible nitric oxide synthase, obesity Abbreviations: Akt, protein kinase B; CD36, cluster of differentiation 36; CHD, coronary heart disease; CV, cardiovascular; CVD, cardiovascular disease; DMT2, diabetes mellitus type 2; ERα, oestrogen receptor-α; ERs, oestrogen receptors; ERK1/2, extracellular signalregulated kinases 1/2; FFA, free fatty acids; HF, high fat; HOMA-IR, HOMA-index of insulin resistance; HOMA-β, HOMA-index of β-cell function; IκB, inhibitor of NFκB; iNOS, inducible nitric oxide synthase; IR, insulin resistance; NFκB-p50, the p50 subunit of nuclear factor-κB; TES, N-[Tris(hydroxymethyl)methyl]-2-aminoethanesulfonic acid; TG, triglycerides VSMCs, vascular smooth muscle cells.

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Section: Interestingly Mariappan Et Al Reported Increased Nfκb Exprcontrasting

confidence: 54%

Influence of a High-Fat Diet on Cardiac iNOS in Female Rats

Jovanović

Sudar-Milovanović

Obradović

et al. 2017

CVP

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“…As shown in Fig. 4, A and B, treatment with either agent promoted phosphorylation of eNOS at Ser-1179 by nearly 50% with a subsequent decrease in phosphorylation of eNOS at Thr-497 by 40%, consistent with reported values (21,22). However, in this case, treatment with calcium ionophore or thapsigargin demonstrated an increase in phosphorylation at AS Ser-328 (ϳ60%) (Fig.…”

Section: Identification Of the Argininosuccinate Synthase Ser-328supporting

confidence: 65%

Protein Kinase Cα Phosphorylates a Novel Argininosuccinate Synthase Site at Serine 328 during Calcium-dependent Stimulation of Endothelial Nitric-oxide Synthase in Vascular Endothelial Cells

Haines

Corbin

Pendleton

et al. 2012

Journal of Biological Chemistry

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Background: Argininosuccinate synthase (AS) is critical for endothelial nitric oxide production, yet little is known about its regulation. Results: AS Ser-328 phosphorylation increased with calcium stimulation and decreased with PKC␣ interference. Conclusion: PKC␣ phosphorylates AS at Ser-328 under calcium-dependent stimulatory conditions to support nitric oxide production. Significance: Knowledge of how AS is regulated is essential in understanding nitric oxide homeostasis.

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“…CaMKII also activates NOX5 (1376). Nevertheless, endothelial ERK1/2 activated by PYK2 partially overcomes ANG II-induced endothelial eNOS dysfunction by enhancing eNOS activity through phosphorylation of Ser633 (Ser635 in bovine endothelial cells) (1736,1737,1994). Endothelial PYK2 also mediates Ras and ERK1/2 activation mediated by LPC (1488), and LPA (lysophosphatidic acid), as well as the bradykinin receptor (426).…”

Section: Physiologic and Atherogenic Consequences Of Pyk2 Signalingmentioning

confidence: 99%

Molecular Biology of Atherosclerosis

Hopkins

2013

Physiological Reviews

371

344

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At least 468 individual genes have been manipulated by molecular methods to study their effects on the initiation, promotion, and progression of atherosclerosis. Most clinicians and many investigators, even in related disciplines, find many of these genes and the related pathways entirely foreign. Medical schools generally do not attempt to incorporate the relevant molecular biology into their curriculum. A number of key signaling pathways are highly relevant to atherogenesis and are presented to provide a context for the gene manipulations summarized herein. The pathways include the following: the insulin receptor (and other receptor tyrosine kinases); Ras and MAPK activation; TNF-␣ and related family members leading to activation of NF-B; effects of reactive oxygen species (ROS) on signaling; endothelial adaptations to flow including G protein-coupled receptor (GPCR) and integrin-related signaling; activation of endothelial and other cells by modified lipoproteins; purinergic signaling; control of leukocyte adhesion to endothelium, migration, and further activation; foam cell formation; and macrophage and vascular smooth muscle cell signaling related to proliferation, efferocytosis, and apoptosis. This review is intended primarily as an introduction to these key signaling pathways. They have become the focus of modern atherosclerosis research and will undoubtedly provide a rich resource for future innovation toward intervention and prevention of the number one cause of death in the modern world.

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Endoplasmic Reticulum Ca2+ Release Modulates Endothelial Nitric-oxide Synthase via Extracellular Signal-regulated Kinase (ERK) 1/2-mediated Serine 635 Phosphorylation

Cited by 34 publications

References 30 publications

Influence of a High-Fat Diet on Cardiac iNOS in Female Rats

Influence of a High-Fat Diet on Cardiac iNOS in Female Rats

Protein Kinase Cα Phosphorylates a Novel Argininosuccinate Synthase Site at Serine 328 during Calcium-dependent Stimulation of Endothelial Nitric-oxide Synthase in Vascular Endothelial Cells

Molecular Biology of Atherosclerosis

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