Insulin-Dependent Activation of Endothelial Nitric Oxide Synthase Is Impaired by O-Linked Glycosylation Modification of Signaling Proteins in Human Coronary Endothelial Cells

Federici, Massimo; Menghini, Rossella; Mauriello, Alessandro; Hribal, Marta Letizia; Ferrelli, Francesca; Lauro, Davide; Sbraccia, Paolo; Spagnoli, Luigi Giusto; Sesti, Giorgio; Lauro, Renato

doi:10.1161/01.cir.0000023043.02648.51

Cited by 309 publications

(253 citation statements)

References 38 publications

Supporting

Mentioning

234

Contrasting

Unclassified

Order By: Relevance

“…eNOS was affinity purified from hearts of ob/ob mice (A; n ϭ 4) and fructose-fed rats (B; n ϭ 4) and immunoblotted with antibodies to phosphorylated S1176 (human S1177). addition, other studies have shown that high glucose does not affect eNOS phosphorylation at this residue (38) or results in decreased phosphorylation via O-linked glycosylation (8). We next addressed whether insulin resistance influences phosphorylation of eNOS at other residues.…”

Section: Discussionmentioning

confidence: 95%

Insulin resistance does not diminish eNOS expression, phosphorylation, or binding to HSP-90

Fulton

Harris

Kemp

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

.-Previously, using an animal model of syndrome X, the obese Zucker rat (OZR), we documented impaired endothelium-dependent vasodilation. The aim of this study was to determine whether reduced expression or altered posttranslational regulation of endothelial nitric oxide synthase (eNOS) underlies the vascular dysfunction in OZR rats. There was no significant difference in the relative abundance of eNOS in hearts, aortas, or skeletal muscle between lean Zucker rats (LZR) and OZR regardless of age. There was no difference in eNOS mRNA levels, as determined by real-time PCR, between LZR and OZR. The inability of insulin resistance to modulate eNOS expression was also documented in two additional in vivo models, the ob/ob mouse and the fructose-fed rat, and in vitro via adenoviral expression of protein tyrosine phosphatase 1B in endothelial cells. We next investigated whether changes in the acute posttranslational regulation of eNOS occurs with insulin resistance. Phosphorylation of eNOS at S632 (human S633) and T494 was not different between LZR and OZR; however, phosphorylation of S1176 was significantly enhanced in OZR. Phosphorylation of S1176 was not different in the ob/ob mouse or in fructose-fed rats. The association of heat shock protein 90 with eNOS, a key regulatory step controlling nitric oxide and aberrant O 2 Ϫ production, was not different between OZR and LZR. Taken together, these results suggest that changes in eNOS expression or posttranslation regulation do not underlie the vascular dysfunction seen with insulin resistance and that other mechanisms, such as altered localization, reduced availability of cofactors, substrates, and the elevated production of O 2 Ϫ , may be responsible. syndrome X; Zucker; obesity INSULIN RESISTANCE, a prediabetic condition associated with obesity, is increasing at an alarming rate in Western cultures (26,30). Diabetes increases the incidence of many vasculopathies, including atherosclerosis, microvascular disease, and poor wound healing (44, 47). Of even greater concern is the mounting evidence that insulin-resistant states, independent of frank diabetes, also promote vascular dysfunction (43, 52). Thus the effect of insulin resistance on vascular signaling mechanisms is an area of increasing scrutiny. Insulin-resistant states and diabetes are associated with reduced endothelium-dependent relaxation, and this dysfunction of the endothelium is highly correlated with future cardiovascular events (1,14,34,49). In the obese Zucker rat (OZR), we previously showed that endothelium-dependent relaxation is impaired (14); however, the mechanisms underlying reduced synthesis or action of nitric oxide (NO) remain to be established.Endothelium-dependent relaxation is mediated by the synthesis and subsequent diffusion of NO from the endothelium to the underlying smooth muscle (21, 35). Of the three NO synthases (NOS), the endothelial isoform (eNOS) is uniquely positioned within the vascular endothelium and alone is responsible for endothelium-dependent NO-mediated relaxation (20)....

show abstract

Section: Discussionmentioning

confidence: 95%

Insulin resistance does not diminish eNOS expression, phosphorylation, or binding to HSP-90

Fulton

Harris

Kemp

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

show abstract

“…IRS-1 is a good substrate of OGT and became highly modified with O-GlcNAc in both control and insulin-activated samples. Several groups have shown that IRS-1 is modified by O-GlcNAc in vivo (17,18,22). IRS-2 is also a substrate for OGT.…”

Section: Irs-1 Irs-2 and Pdk1 Of The Pi3k/akt Insulin Signalingmentioning

confidence: 99%

“…A few studies have shown that increased O-GlcNAc dampens AKT activity in response to insulin stimulation of insulin target tissues, such as adipocytes and muscle and endothelial cells (15)(16)(17)(18). Recent studies have demonstrated that a specific increase in global O-GlcNAc levels, induced by inhibiting O-GlcNAcase, in the absence of hyperglycemia, causes insulin resistance directly (16,19,20).…”

mentioning

confidence: 99%

Regulation of Insulin Receptor Substrate 1 (IRS-1)/AKT Kinase-mediated Insulin Signaling by O-Linked β-N-Acetylglucosamine in 3T3-L1 Adipocytes

Whelan¹,

Dias²,

Thiruneelakantapillai³

et al. 2010

Journal of Biological Chemistry

150

121

View full text Add to dashboard Cite

“…In bovine aortic and human coronary endothelial cells, aortas isolated from diabetic animals, and carotid plaques from diabetic patients, basal eNOS activity is inhibited by hyperglycemia through O-linked GlcNAc modification of eNOS, which reciprocally decreases phosphorylation of Ser-1177. 39,40 Recent studies in diabetes-associated ED using a rat model of type 1 diabetes demonstrated decreased phosphorylation of eNOS in the penis specifically at Ser-1177 in association with decreased erectile capability. 18 These studies not only demonstrate that O-GlcNAc modification of eNOS significantly contributes to ED associated with diabetes, but also provide the first evidence for the physiologic relevance of O-GlcNAc modification of eNOS in the diabetic vascular tissue.…”

Section: Enos Expressionmentioning

confidence: 99%

Endothelial dysfunction in diabetic erectile dysfunction

2006

View full text Add to dashboard Cite

Erectile dysfunction (ED) is highly prevalent in diabetes mellitus. Pathophysiological mechanisms underlying diabetes-associated ED are in large part due to endothelial dysfunction, which functionally refers to the inability of the endothelium to produce vasorelaxing messengers and to maintain vasodilation and vascular homeostasis. The precise mechanisms leading to endothelial dysfunction in the diabetic vasculature, including the penis, are not yet fully understood. Hyperglycemia affects endothelial nitric oxide synthase activity and nitric oxide production/ bioavailability, nitric oxide-independent relaxing factors, oxidative stress, production and/or action of hormones, growth factors and/or cytokines, and generation and activity of opposing vasoconstrictors. Considering recent advances in the field of vascular biology and diabetes, the emphasis in this review is placed on the mechanisms of hyperglycemia-induced endothelial dysfunction in the pathophysiology of diabetes-associated ED.

show abstract

Insulin-Dependent Activation of Endothelial Nitric Oxide Synthase Is Impaired by O-Linked Glycosylation Modification of Signaling Proteins in Human Coronary Endothelial Cells

Cited by 309 publications

References 38 publications

Insulin resistance does not diminish eNOS expression, phosphorylation, or binding to HSP-90

Insulin resistance does not diminish eNOS expression, phosphorylation, or binding to HSP-90

Regulation of Insulin Receptor Substrate 1 (IRS-1)/AKT Kinase-mediated Insulin Signaling by O-Linked β-N-Acetylglucosamine in 3T3-L1 Adipocytes

Endothelial dysfunction in diabetic erectile dysfunction

Contact Info

Product

Resources

About