C-peptide exerts cardioprotective effects in myocardial ischemia-reperfusion

Young, Lindon H.; Ikeda, Yasuhiko; Scalia, Rosario; Lefer, Allan M.

doi:10.1152/ajpheart.2000.279.4.h1453

Cited by 60 publications

(63 citation statements)

References 32 publications

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“…As a consequence, the number of rolling, adhering and transmigrated leucocytes also decreased upon C-peptide administration to the animals. In another model of vascular injury, systemic administration of C-peptide decreased polymorphonuclear leucocyte infiltration in isolated rat hearts following ischaemia-reperfusion injury and restored cardiac contractile function and postreperfusion coronary heart flow [27]. Our group has reported on the anti-inflammatory activity of C-peptide in high-glucose endothelial dysfunction, when C-peptide decreased vascular cell adhesion molecule 1 (VCAM1) mRNA expression and protein levels, and reduced secretion of IL-8 and monocyte chemoattractant factor (MCP)-1 by HAEC to the basal levels measured under normal glucose concentrations [29].…”

Section: Discussionmentioning

confidence: 97%

“…As type 1 diabetes patients typically lack physiological levels of insulin and C-peptide, this is considered an important factor in the pathophysiology of diabetic complications [24][25][26]. C-peptide has been shown to improve endothelial dysfunction and systemic inflammation in several in vivo and in vitro models of inflammation-mediated vascular injury by reducing expression of genes encoding endothelial cell adhesion molecules, inflammatory cytokine production and adherence and transmigration of leucocytes [27][28][29][30]. Although the exact mechanism(s) underlying the antiinflammatory activity of C-peptide is not known, there is evidence that C-peptide affects NF-κB activation [29,31].…”

Section: Introductionmentioning

confidence: 99%

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C-peptide reduces high-glucose-induced apoptosis of endothelial cells and decreases NAD(P)H-oxidase reactive oxygen species generation in human aortic endothelial cells

et al. 2011

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Aims/hypothesis Reactive oxygen species (ROS) generated during hyperglycaemia are implicated in the development of diabetic vascular complications. High glucose increases oxidative stress in endothelial cells and induces apoptosis. A major source of ROS in endothelial cells exposed to glucose is the NAD(P)H oxidase enzyme. Several studies demonstrated that C-peptide, the product of proinsulin cleavage within the pancreatic beta cells, displays anti-inflammatory effects in certain models of vascular dysfunction. However, the molecular mechanism underlying this effect is unclear. We hypothesised that C-peptide reduces glucose-induced ROS generation by decreasing NAD(P)H oxidase activation and prevents apoptosis Methods Human aortic endothelial cells (HAEC) were exposed to 25 mmol/l glucose in the presence or absence of C-peptide and tested for protein quantity and activity of caspase-3 and other apoptosis markers by ELISA, TUNEL and immunoblotting. Intracellular ROS were measured by flow cytometry using the ROS sensitive dye chloromethyl-2′,7′-dichlorodihydrofluorescein diacetate (CM-H 2 -DCDFA). NAD(P)H oxidase activation was assayed by lucigenin. Membrane and cytoplasmic levels of the NAD (P)H subunit ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1) (RAC-1) and its GTPase activity were studied by immunoblotting and ELISA. RAC-1 (also known as RAC1) gene expression was investigated by quantitative real-time PCR. Results C-peptide significantly decreased caspase-3 levels and activity and upregulated production of the antiapoptotic factor B cell CLL/lymphoma 2 (BCL-2). Glucose-induced ROS production was quenched by C-peptide and this was associated with a decreased NAD (P)H oxidase activity and reduced RAC-1 membrane production and GTPase activity. Conclusions/interpretation In glucose-exposed endothelial cells, C-peptide acts as an endogenous antioxidant molecule by reducing RAC-1 translocation to membrane and NAD (P)H oxidase activation. By preventing oxidative stress, C-peptide protects endothelial cells from glucose-induced apoptosis.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

C-peptide reduces high-glucose-induced apoptosis of endothelial cells and decreases NAD(P)H-oxidase reactive oxygen species generation in human aortic endothelial cells

et al. 2011

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“…In humans, descent of the dicrotic notch of digital and aortic pulse waves has been observed with nitrate and albuterol administration, as well as with exercise (10,26,29,39,42,46). This finding is mediated through the action of NO, since inhibition of NO synthesis with N G -nitro-L-arginine methyl ester (L-NAME) or N G -monomethyl-L-arginine prevents descent of the dicrotic notch after acetylcholine or albuterol administration in rabbits and humans, respectively (26, 52).Our purpose was to assess whether pG z applied to rats serves as a means of producing endothelial-dependent vasodilatation and to test whether such an effect is mediated, in part, via the well-known shear stress induced Akt/phosphatidylinositol 3-kinase (PI3K) pathway for NO production (13,55,57). …”

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confidence: 99%

“…Our purpose was to assess whether pG z applied to rats serves as a means of producing endothelial-dependent vasodilatation and to test whether such an effect is mediated, in part, via the well-known shear stress induced Akt/phosphatidylinositol 3-kinase (PI3K) pathway for NO production (13,55,57).…”

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confidence: 99%

Low-amplitude pulses to the circulation through periodic acceleration induces endothelial-dependent vasodilatation

Uryash

Wu²,

Bassuk³

et al. 2009

Journal of Applied Physiology

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Uryash A, Wu H, Bassuk J, Kurlansky P, Sackner MA, Adams JA. Low-amplitude pulses to the circulation through periodic acceleration induces endothelial-dependent vasodilatation. J Appl Physiol 106: 1840 -1847, 2009. First published March 26, 2009 doi:10.1152/japplphysiol.91612.2008.-Low-amplitude pulses to the vasculature increase pulsatile shear stress to the endothelium. This activates endothelial nitric oxide (NO) synthase (eNOS) to promote NO release and endothelial-dependent vasodilatation. Descent of the dicrotic notch on the arterial pulse waveform and a-to-b ratio (a/b; where a is the height of the pulse amplitude and b is the height of the dicrotic notch above the end-diastolic level) reflects vasodilator (increased a/b) and vasoconstrictor effects (decreased a/b) due to NO level change. Periodic acceleration (pG z) (motion of the supine body head to foot on a platform) provides systemic additional pulsatile shear stress. The purpose of this study was to determine whether or not pG z applied to rats produced endothelial-dependent vasodilatation and increased NO production, and whether the latter was regulated by the Akt/phosphatidylinositol 3-kinase (PI3K) pathway. Male rats were anesthetized and instrumented, and pG z was applied. Sodium nitroprusside, N G -nitro-L-arginine methyl ester (L-NAME), and wortmannin (WM; to block Akt/PI3K pathway) were administered to compare changes in a/b and mean aortic pressure. Descent of the dicrotic notch occurred within 2 s of initiating pG z. Dose-dependent increase of a/b and decrease of mean aortic pressure took place with SNP. L-NAME produced a dose-dependent rise in mean aortic pressure and decrease of a/b, which was blunted with pG z. In the presence of WM, pGz did not decrease aortic pressure or increase a/b. WM also abolished the pG z blunting effect on blood pressure and a/b of L-NAME-treated animals. eNOS expression was increased in aortic tissue after pG z. This study indicates that addition of low-amplitude pulses to circulation through pG z produces endothelial-dependent vasodilatation due to increased NO in rats, which is mediated via activation of eNOS, in part, by the Akt/PI3K pathway. vascular resistance; N G -nitro-L-arginine methyl ester, wortmannin; nitric oxide ADDED LOW-AMPLITUDE PULSES to the vasculature were generated with periodic acceleration (pG z ). pG z is produced by a motorized platform that repetitively moves the horizontally oriented body sinusoidally in a head to foot direction. Inertia of fluid as the body accelerates and decelerates adds a small-amplitude pulse to the circulation that is superimposed on the natural pulse, increasing pulsatile shear stress to the endothelium (3, 6, 7). In large-animal models, increased pulsatile shear stress activates endothelial nitric oxide (NO) synthase (eNOS) to release NO into the circulation, which, in turn, induces endothelial-dependent pulmonary and systemic vasodilatation, as well as increasing organ blood flows (3,5,6). pG z applied to anesthetized swine increases serum nitrite, which is ...

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“…Conversely, in experimental Type 1 diabetes, a situation with complete insulin and C-peptide deprivation, short term infusion of C-peptide increases renal functional reserve, reduces protein leakage and improves hyperfiltration [5]. At the cellular level, the effects of C-peptide include stimulation of Na + ,K + -ATPase activity [6,7] and activation of endothelial nitric oxide synthase [8,9,10]. The C-peptide signal transduction pathway is thought to involve an heteromultimeric G-protein-mediated increase in intracellular Ca 2+ leading to protein kinase C (PKC) and mitogen-activated protein kinase activation [4,6,11].…”

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confidence: 99%

C-Peptide stimulates Na+,K+-ATPase activity via PKC alpha in rat medullary thick ascending limb

et al. 2003

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Aims/hypothesis. C-peptide, the cleavage product of proinsulin processing exerts physiological effects including stimulation of Na + ,K + -ATPase in erythrocytes and renal proximal tubules. This study was undertaken to assess the physiological effects of connecting peptide on Na + ,K + -ATPase activity in the medullary thick ascending limb of Henle's loop. Methods. Na + ,K + -ATPase activity was measured as the ouabain-sensitive generation of 32 Pi from γ[ 32 P]-ATP and 86 Rb uptake on isolated rat medullary thick ascending limbs. The cell-surface expression of Na + ,K + -ATPase was evaluated by Western blotting of biotinylated proteins, and its phosphorylation amount was measured by autoradiography. The membrane-associated fraction of protein kinase C isoforms was evaluated by Western blotting. Results. Rat connecting peptide concentration-dependently stimulated Na + ,K + -ATPase activity with a threshold at 10 −9 mol/l and a maximal effect at 10 −7 mol/l. C-peptide (10 −7 mol/l) already stimulates Na + ,K + -ATPase activity after 5 min with a plateau from 15 to 60 min. C-peptide (10 −7 mol/l) stimulated Na + ,K + -ATPase activity and 86 Rb uptake to the same extent, but did not alter Na + ,K + -ATPase cell surface expression. The stimulation of Na + ,K + -ATPase activity was associated with an increase in Na + ,K + -ATPase α-subunit phosphorylation and both effects were abolished by a specific protein kinase C inhibitor. Furthermore, connecting peptide induced selective membrane translocation of PKC-α. Conclusion/interpretation. This study provides evidence that in rat medullary thick ascending limb, C-peptide stimulates Na + ,K + -ATPase activity within a physiological concentration range. This effect is due to an increase in Na + ,K + -ATPase turnover rate that is most likely mediated by protein kinase C-α phosphorylation of the Na + ,K + -ATPase α-subunit, suggesting that C-peptide could control Na + reabsorption during non-fasting periods. [Diabetologia (2003) 46:124-131]

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C-peptide exerts cardioprotective effects in myocardial ischemia-reperfusion

Cited by 60 publications

References 32 publications

C-peptide reduces high-glucose-induced apoptosis of endothelial cells and decreases NAD(P)H-oxidase reactive oxygen species generation in human aortic endothelial cells

C-peptide reduces high-glucose-induced apoptosis of endothelial cells and decreases NAD(P)H-oxidase reactive oxygen species generation in human aortic endothelial cells

Low-amplitude pulses to the circulation through periodic acceleration induces endothelial-dependent vasodilatation

C-Peptide stimulates Na+,K+-ATPase activity via PKC alpha in rat medullary thick ascending limb

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