Nitric oxide availability in diabetes mellitus

Honing, Marina L. H.; Morrison, Paul J.; Banga, Jan Dirk; Stroes, Erik S.G.; Rabelink, Ton J.

doi:10.1002/(sici)1099-0895(1998090)14:3<241::aid-dmr216>3.0.co;2-r

Cited by 176 publications

(108 citation statements)

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“…This is one of the likely mechanisms of NO-mediated C-peptide action in vivo. Since endothelium-derived NO plays an important part in maintaining vascular tone and endothelial cell integrity [36], our observations increase understanding of the physiological and pathophysiological roles of C-peptide.…”

Section: Discussionmentioning

confidence: 73%

Proinsulin C-peptide increases nitric oxide production by enhancing mitogen-activated protein-kinase-dependent transcription of endothelial nitric oxide synthase in aortic endothelial cells of Wistar rats

et al. 2003

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Aims/hypothesis. Recent studies have suggested that proinsulin C-peptide improves vascular functions, possibly through nitric oxide (NO) production. To clarify the molecular mechanisms of vascular NO production induced by C-peptide, we examined the effects of C-peptide on NO production and NO synthase expression in rat aortic endothelial cells in connection with mitogen-activated protein kinase (MAPK) activation. Methods. Aortic endothelial cells were isolated from female Wistar rats, cultured to confluence, and serum-starved for 24 h before treatment with C-peptide. Nitric oxide production was measured by the DAF-2 fluorescence dye method and relative amounts of endothelial nitric oxide synthase (eNOS) protein and its mRNA were semi-quantified by western blot and RT-PCR analyses respectively. Activation of MAPK was estimated by western blot detection of activity-related phosphorylation and in vitro kinase assay. Results. Stimulation of cells with C-peptide for 3 h doubled NO production, which was suppressed by the NO synthase inhibitor, N G -nitro-L-arginine methyl ester (L-NAME). Stimulation also increased mRNA and protein contents of eNOS in a manner sensitive to the transcription inhibitor actinomycin D. It did not affect inducible NO synthase mRNA. C-peptide also induced rapid phosphorylation and activation of extracellular signal-regulated kinase (ERK, also known as p44/42MAPK), but not of p38MAPK. In cells pretreated with the ERK inhibitor PD98059 the C-peptide-elicited increase of NO production and eNOS was abrogated in a dose-dependent manner; suppression of ERK phosphorylation induced by C-peptide also occurred. Conclusions/interpretation. Our results show that Cpeptide increases NO production by increasing eNOS protein contents through ERK-dependent up-regulation of eNOS gene transcription. This could explain some actions of C-peptide on the vasculature, indicating a pivotal role for C-peptide in vascular homeostasis. [Diabetologia (2003[Diabetologia ( ) 46:1698[Diabetologia ( -1705

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Section: Discussionmentioning

confidence: 73%

Proinsulin C-peptide increases nitric oxide production by enhancing mitogen-activated protein-kinase-dependent transcription of endothelial nitric oxide synthase in aortic endothelial cells of Wistar rats

et al. 2003

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“…2,3 Interestingly, one of these studies 3 found that hyperinsulinemia without diabetes also resulted in enhanced neointima formation after vascular injury, a finding that underscores the pivotal role of elevated insulin as a vascular pathogen. Other studies have reported that diabetes may be associated with NO deficiency, 16 a finding that could explain the tendency of insulin to enhance neointimal formation in vascular disease.…”

Section: Discussionmentioning

confidence: 93%

“…15 Of further relevance is the finding that type II diabetes may be associated with a deficit of NO; moreover, amelioration of the consequences of hyperinsulinemia by NO has also been reported. 16 Potential biochemical mechanisms that could explain the inhibitory effect of NO on cell motility include an inhibition of Raf activity, leading to an inhibition of mitogen-activated protein kinase (MAPK) activity. 17 More recently, we have reported that NO increases the activity of protein tyrosine phosphatase 1B (PTP1B), a tyrosine phosphatase that targets several focal adhesion proteins, and using antisense oligodeoxynucleotides, we have found that the capacity of NO to decrease baseline cell motility may be mediated via increased PTP1B activity.…”

mentioning

confidence: 99%

NO Attenuates Insulin Signaling and Motility in Aortic Smooth Muscle Cells via Protein Tyrosine Phosphatase 1B–Mediated Mechanism

Nair

Yan

Hassid

2002

ATVB

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Objective-Hyperinsulinemia is a significant risk factor for the pathogenesis of vascular disease. Protein tyrosine phosphatase 1B (PTP1B) has been recognized as a modulator of insulin signaling in nonvascular cells, and we have recently reported that NO increases the activity of PTP1B in rat vascular smooth muscle cells. In the present study, we tested the hypothesis that NO attenuates insulin-stimulated cell motility via a PTP1B-mediated mechanism involving downregulation of insulin signal transduction. Methods and Results-Treatment of primary aortic smooth muscle cells from newborn rats with the NO donor S-nitroso-N-acetylpenicillamine reduced cell motility, tyrosine phosphorylation levels of insulin receptor ␤ subunit and insulin receptor substrate-1, and extracellular signal-regulated kinase activity. Overexpression of wild-type PTP1B via an adenoviral vector blocked the capacity of insulin to stimulate cell motility and insulin receptor phosphorylation, whereas expression of a dominant-negative mutant of PTP1B attenuated the capacity of NO to decrease cell motility. Conclusions-Our findings indicate that activation of PTP1B is necessary and sufficient to account for the capacity of NO to decrease insulin-stimulated signal transduction and cell motility in cultured aortic smooth muscle cells. The results could explain the capacity of NO to oppose neointima formation in states of hyperinsulinemia. Key Words: cell signaling Ⅲ signal transduction Ⅲ atherosclerosis Ⅲ growth factors Ⅲ type 2 diabetes T ype II diabetes is a major risk factor for the pathogenesis of vascular disease, including that associated with hypertension and atherosclerosis. That diabetes increases the frequency of coronary vessel restenosis occurring after angioplasty is also well established. 1 Most forms of vascular disease in conduit arteries manifest neointimal enlargement, and although type II diabetes is associated with hyperglycemia as well as hyperinsulinemia, recent studies have suggested that elevated insulin levels may be the more important factor in the pathogenesis of neointimal enlargement. 2,3 The proliferation and motility of vascular smooth muscle cells is regulated in reciprocal fashion by stimulators (eg, fibroblast growth factor, platelet-derived growth factor, and heparin-binding epidermal growth factor) and inhibitors of mitogenesis or motility (eg, prostanoids, heparin, atrial natriuretic factor, and transforming growth factor-␤). 4 -7 Similar to many other growth factors, insulin has the capacity to stimulate cell motility in vitro, which could explain the pathogenesis of diabetic neointimal growth. 3,8 Early studies from several laboratories, including ours, have reported that NO decreases vascular smooth muscle cell proliferation in subcultured cells from adult rats or in primary cultures from newborn rats. 9,10 More recent studies have reported that NO also inhibits aortic smooth muscle cell motility. 11,12 Furthermore, several studies in vivo have reported that NO, or its precursor arginine, attenuates neointima ...

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“…In a non-diseased cardiovascular system, O 2 ·-, NO, and other pro-oxidants and anti-oxidants are regulated. With onset of cardiovascular disease, the pro-oxidant/anti-oxidant balance is lost and pro-oxidants increase with an eventual decrease in anti-oxidant availability and antioxidant enzyme expression during chronic oxidative stress (Honing et al 1998;Hamilton et al 2004;Muller et al 2004), notably the RNS nitric oxide (NO). The oxidant imbalance is normally associated with increased O 2 ·-and decreased NO availability (Iuchi et al 2003;Zhang et al 2003).…”

Section: Oxidative Stressmentioning

confidence: 99%