Stimulation of endothelial nitric oxide synthase by proinsulin C-peptide

Wallerath, Thomas; Kunt, T.; Forst, Thomas; Closs, Ellen I.; Lehmann, Ralf; Flohr, Thomas; Gabriel, Matthias; Schäfer, Dirk; Göpfert, Andrea; Pfützner, Andreas; Beyer, J.; Förstermann, Ulrich

doi:10.1016/j.niox.2003.08.004

Cited by 110 publications

(121 citation statements)

References 33 publications

Supporting

Mentioning

112

Contrasting

Unclassified

Order By: Relevance

“…At the same time, activated PKC-δ and -ɛ could phosphorylate and activate other downstream target proteins such as Ca 2+ channels [41,42]. L-Type Ca 2+ channels have been reported to be positively modulated by novel PKC isoforms [41,43] and it is established that C-peptide is capable of eliciting increases in intracellular Ca 2+ concentration [2,5,6]. In the present study we found that the Ca 2+ channel blockers verapamil and nifedipine abolished the effect of C-peptide on ERK1/2 phosphorylation, indicating that C-peptide stimulation results in an influx of Ca 2+ rather than in the release of intracellular Ca +2 stores.…”

Section: Discussionmentioning

confidence: 99%

“…There is evidence to suggest that C-peptide binds to a G-protein-coupled membrane binding site on a number of different cell types [1], thereby triggering Ca 2+ -dependent intracellular signalling pathways [2] including the mitogen-activated protein (MAP) kinase cascade [3,4]. This results in subsequent activation of both Na + , K + -ATPase [5][6][7] and endothelial nitric oxide synthase (eNOS) [5][6][7][8]. Activation of these enzyme systems is of particular interest in diabetes, since both are reported to be deficient in this disorder [9][10][11][12].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

C-peptide stimulates ERK1/2 and JNK MAP kinases via activation of protein kinase C in human renal tubular cells

et al. 2004

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

C-peptide stimulates ERK1/2 and JNK MAP kinases via activation of protein kinase C in human renal tubular cells

et al. 2004

View full text Add to dashboard Cite

show abstract

“…Therefore, C-peptide-induced increase of blood flow in kidney and skin observed in patients with type 1 diabetes [5,9] may be attributed to vasodilatory effect of C-peptide through directly acting on vascular endothelial cells [13,14,30].…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, C-peptide acts on endothelial cells to stimulate Ca 2+ -dependent NO synthase activity [30] and also its transcription through the mitogen-activated protein kinase pathways [13,14]. In addition to these NO-dependent C-peptide action, our previous results that antagonistic effect of C-peptide on sympathetically mediated response was blocked by prior treatment with atropine, a parasympatholytic drug, [20] suggest that Cpeptide might directly activate the parasympathetic nervous system and also influence indirectly the sympathetic nervous system or its effector function.…”

Section: Introductionmentioning

confidence: 99%

Proinsulin C-peptide activates vagus efferent output in rats

et al. 2005

View full text Add to dashboard Cite

The aim of this study was to examine the effect of proinsulin C-peptide on the autonomic nervous systems in rats. Intravenous administration of C-peptide gradually increased electrophysiological activity of the vagus nerves into the stomach and pancreas for at least 90 min. It also slightly increased gastric acid secretion that was suppressed by the treatment with atropine. Intraperitoneal injection of C-peptide did not affect the basal and stress-induced norepinephrine turnover rate, a biochemical index of sympathetic nerve activity. These results indicate that C-peptide increases parasympathetic nerve activity without affecting sympathetic nerve activity. This could explain, at least in part, the ameliorating effects of C-peptide on impaired cardiac autonomic nerve functions in patients with type 1 diabetes.

show abstract

“…Activation of the Na -K pump by C-peptide was also demonstrated in man (15), but whether the protection by C-peptide against diabetic complications is mediated by this mechanism remains unclear. Of interest, recent findings indicate that C-peptide increases calcium influx and stimulates endothelial nitric oxide synthase (16,17), possibly through the activation of the mitogen-activated protein (MAP) kinase (18).…”

Section: Introductionmentioning

confidence: 99%

C-peptide increases the expression of vasopressin-activated calcium-mobilizing receptor gene through a G protein-dependent pathway

et al. 2005

View full text Add to dashboard Cite

Objective: Although an increasing number of reports suggest that physiological concentrations of C-peptide protect against the development of diabetic nephropathy, possibly through the modulation of Na -K pump activity, the intracellular pathways controlled by C-peptide are still unrecognized. C-peptide and vasopressin share similar intracellular effects including the activation of calcium influx and endothelial nitric oxide synthase. Both hormones stimulate also the activity of Na-K pump activity. Whether the activity of C-peptide is mediated by the recently identified vasopressinactivated calcium-mobilizing receptor (VACM-1) has never been previously investigated. Design and methods: To clarify this issue, we evaluated the effect of C-peptide on VACM-1 RNA (measured by semiquantitative RT-PCR) and protein expression (measured by immunoblotting) in human skin fibroblasts (where a specific binding of C-peptide was demonstrated) and in human mesangial cells, the cellular target of diabetic nephropathy. Results: C-peptide-induced activation of VACM-1 was demonstrated in fibroblasts from six healthy individuals (0.51^0.1 vs 1.48^0.4, arbitrary units^S.E., P ¼ 0.025). This finding was paralleled by an increased VACM-1 protein expression (5.64^1.0 vs 8.47^1.2, arbitrary units^S.E., P ¼ 0.043). Similar results were confirmed in three independent cultures of human mesangial cells. VACM-1 activation in fibroblasts was insensitive to phosphatidylinositol-3-kinase inhibitor LY294002, but was inhibited by pertussis toxin, suggesting that activation of VACM-1 could be mediated by a G protein-coupled receptor. Conclusions: This study demonstrates for the first time that C-peptide activates VACM-1, possibly through a G protein-coupled receptor. Further studies are needed to clarify whether VACM-1 is involved in the protective effect of C-peptide against the development of diabetic nephropathy.

show abstract

Stimulation of endothelial nitric oxide synthase by proinsulin C-peptide

Cited by 110 publications

References 33 publications

C-peptide stimulates ERK1/2 and JNK MAP kinases via activation of protein kinase C in human renal tubular cells

C-peptide stimulates ERK1/2 and JNK MAP kinases via activation of protein kinase C in human renal tubular cells

Proinsulin C-peptide activates vagus efferent output in rats

C-peptide increases the expression of vasopressin-activated calcium-mobilizing receptor gene through a G protein-dependent pathway

Contact Info

Product

Resources

About