Endothelin-1 induces interleukin-6 release via acctivation of the transcription factor NF-κB in human vascular smooth muscle cells

Browatzki, Michael; Schmidt, Joachim; Kübler, W.; Kranzhöfer, Roger

doi:10.1007/s003950050170

Cited by 145 publications

(104 citation statements)

References 35 publications

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“…Although ET-1 is known to be one of the upstream activators of IL-6, 29 we suggest that this may not be the case in HSVECs stimulated with CRP. This conclusion is based on our observation that IL-6 levels are not attenuated during concurrent ET receptor blockade.…”

Section: Et-1 and Il-6 May Mediate The Proinflammatory Actions Of Crpmentioning

confidence: 61%

Endothelin Antagonism and Interleukin-6 Inhibition Attenuate the Proatherogenic Effects of C-Reactive Protein

et al. 2002

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Background-C-reactive protein (CRP) has been suggested to actively participate in the development of atherosclerosis.In the present study, we examined the role of the potent endothelium-derived vasoactive factor endothelin-1 (ET-1) and the inflammatory cytokine interleukin-6 (IL-6) as mediators of CRP-induced proatherogenic processes. Methods and Results-Saphenous vein endothelial cells (HSVECs) were incubated with human recombinant CRP (25 g/mL, 24 hours) and the expression of vascular cell adhesion molecule (VCAM-1), intracellular adhesion molecule (ICAM-1), and monocyte chemoattractant chemokine-1 was determined. The effects of CRP on LDL uptake were assessed in macrophages using immunofluorescent labeling of CD32 and CD14. In each study, the effect of endothelin antagonism (bosentan) and IL-6 inhibition (monoclonal anti-IL-6 antibodies) was examined. The effects of CRP on the secretion of ET-1 and IL-6 from HSVECs were also evaluated. Incubation of HSVECs with recombinant human CRP resulted in a marked increase in ICAM-1 and VCAM-1 expression (PϽ0.001). Likewise, CRP caused a significant increase in monocyte chemoattractant chemokine-1 production, a key mediator of leukocyte transmigration (PϽ0.001). CRP caused a marked and sustained increase in native LDL uptake by macrophages (PϽ0.05). These proatherosclerotic effects of CRP were mediated, in part, via increased secretion of ET-1 and IL-6 (PϽ0.01) and were attenuated by both bosentan and IL-6 antagonism (PϽ0.01). Conclusions-CRP actively promotes a proatherosclerotic and proinflammatory phenotype. These effects are mediated, in part, via the production of ET-1 and IL-6 and are attenuated by mixed ET A/B receptor antagonism and IL-6 inhibition. Bosentan may be useful in decreasing CRP-mediated vascular disease.

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Section: Et-1 and Il-6 May Mediate The Proinflammatory Actions Of Crpmentioning

confidence: 61%

Endothelin Antagonism and Interleukin-6 Inhibition Attenuate the Proatherogenic Effects of C-Reactive Protein

et al. 2002

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“…41 In that same study, pyrrolidinedithiocarbamate inhibited the ET-1-mediated IL-6 secretion from these cells, which suggests that ET-1 stimulates ROS production. 41 IL-6 has also been shown to potentiate angiotensin II-mediated superoxide production, 42 but whether or not IL-6 potentiates ET-1-mediated superoxide production still has to be thoroughly investigated. Future studies will be needed to explore the involvement of other ROS and inflammatory mediators in the hypertension produced by ET B receptor blockade.…”

Section: Perspectivesmentioning

confidence: 79%

“…39,40 In vitro, ET-1 stimulates secretion of interleukin-6 (IL-6), an inflammatory cytokine, from human vascular smooth muscle cells via activation of NF-B. 41 In that same study, pyrrolidinedithiocarbamate inhibited the ET-1-mediated IL-6 secretion from these cells, which suggests that ET-1 stimulates ROS production. 41 IL-6 has also been shown to potentiate angiotensin II-mediated superoxide production, 42 but whether or not IL-6 potentiates ET-1-mediated superoxide production still has to be thoroughly investigated.…”

Section: Perspectivesmentioning

confidence: 88%

Arterial Pressure Response to the Antioxidant Tempol and ET _B Receptor Blockade in Rats on a High-Salt Diet

Williams

Pollock

2004

Hypertension

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Abstract-We hypothesized that increased superoxide contributes to mean arterial pressure (MAP) regulation in male Sprague-Dawley rats fed a high-salt diet and/or during endothelin (ET B ) receptor blockade. Four groups on either a normal-or a high-salt diet were studied for 1 week: (1) control; (2) tempol, a superoxide dismutase mimetic, in their drinking water (1 mmol/L); (3) A-192621, an ET B antagonist, in their food (10 mg/kg daily); or (4) both tempol and A-192621. Without ET B blockade, tempol had no effect on MAP (telemetry) in rats on the normal-salt diet but significantly reduced MAP in rats on the high-salt diet (100Ϯ3 vs 112Ϯ2 mm Hg, PϽ0.05). On the normal-salt diet, A-192621 increased MAP with or without tempol. Under high-salt conditions, tempol attenuated the increase in MAP produced by A-192621, but only during the initial days of treatment. Plasma 8-isoprostanes were increased in all rats on the high-salt diet and were further increased after 3 days of A-192621 but not after 7 days; tempol inhibited the increase produced by A-192621 but had no influence on the increase produced by high salt. H 2 O 2 excretion was significantly higher in rats on a high-salt diet for the 7-day drug treatment compared with those on a normal-salt diet. Tempol further increased H 2 O 2 excretion in rats on a high-salt diet, an effect accelerated in A-192621-treated rats. These data suggest that blood pressure lowering by tempol in rats on a high-salt diet may be unrelated to reductions in superoxide and that renal H 2 O 2 may account for the limited ability of tempol to attenuate hypertension produced by ET B receptor blockade. Key Words: endothelin Ⅲ oxidative stress Ⅲ blood pressure monitoring Ⅲ prostaglandins Ⅲ hypertension, sodium dependent Ⅲ free radicals R eactive oxygen species (ROS) have been implicated in the development of hypertension and other pathologic processes. There is evidence that increased ROS may contribute to the elevated blood pressure in the spontaneously hypertensive rat; the 2-kidney, 1-clip hypertensive rat; the angiotensin II-infused rat, the deoxycorticosterone acetatesalt rat, and the Dahl salt-sensitive rat. 1-10 Tempol, a superoxide dismutase (SOD) mimetic, has been shown to lower blood pressure in these models of hypertension. [2][3][4][5][6][7][8][9][10] Endothelin (ET-1) is a potent vasoconstrictor when binding to ET A receptors on vascular smooth muscle cells, but ET-1 can also act as a vasodilator when binding to the ET B receptor on endothelial and renal tubular cells, which can then promote natriuresis by inhibiting tubular reabsorption. 11,12 ET B receptors are also beneficial in the regulation of the physiologic effects of ET-1 by removing it from the systemic circulation, thereby limiting ET A receptor activation. 13,14 Chronic ET B receptor blockade increases plasma ET-1 levels and produces saltdependent hypertension. 15 Similarly, in the ET B -deficient rat, both plasma ET-1 concentrations and basal arterial pressure are significantly elevated and are further increased by hi...

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“…33 ET-1 administration has been reported to increase activation of NF-B in cardiac and vascular myocytes and lead to release of cytokine (IL-6) and cardiomyocyte hypertrophy. 34,35 In our model, nuclear NF-B translocation was concurrent with ET-1 overexpression and preceded the activation of cardiac cytokines, suggesting that ET-1 was sufficient to initiate an inflammatory cascade ultimately leading to cardiac dysfunction and death. Given the lack of increase in systemic arterial pressures, cardiac hypertrophy of BT mice was probably a result of a direct effect of ET-1 on cardiomyocytes.…”

Section: Discussionmentioning

confidence: 96%

Conditional Cardiac Overexpression of Endothelin-1 Induces Inflammation and Dilated Cardiomyopathy in Mice

Yang

Gros²,

Kabir³

et al. 2004

Circulation

155

113

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Background-Myocardial expression of endothelin-1 (ET-1) and its receptors ET A and ET B is increased in heart failure.However, the role of ET-1 and its signaling pathways in the pathogenesis of myocardial diseases is unclear. Methods and Results-Human ET-1 cDNA was placed downstream of a promoter responsive to a doxycycline (DOX)-regulated transcriptional activator (tTA). This line (ET ϩ ) was bred with one harboring cardiac myocyterestricted expression of tTA (␣MHC-tTA). Myocardial ET-1 peptide levels were significantly increased in binary transgenic (BT, ET ϩ /tTA ϩ ) compared with nonbinary transgenic (NBT, ET ϩ /tTA Ϫ ; ET Ϫ /tTA ϩ ; ET Ϫ /tTA Ϫ ) or DOX-treated BT littermates (40.1Ϯ4.7 versus 2.6Ϯ1.2 fmol/mL, PϽ0.003). BT mice demonstrated progressive mortality between 5 and 11 weeks after DOX withdrawal, associated with left ventricular dilatation and contractile dysfunction (peak ϩdP/dT, 4673Ϯ468 versus 5585Ϯ658 mm Hg/s, PϽ0.05). An interstitial inflammatory infiltrate, including macrophages and T lymphocytes, was evident in the myocardium of BT mice, associated with sequential increases in nuclear factor-B translocation and expression of tumor necrosis factor-␣, interferon-␥, interleukin-1 and interleukin-6. Significant prolongation of survival was observed with the combined ET A /ET B antagonist LU420627 (nϭ8, PϽ0.05) in BT mice but not the ET A -selective antagonist LU135252 (nϭ5, Pϭ0.9), consistent with an important role for ET B in this model. Conclusions-These are the first data to demonstrate that cardiac overexpression of ET-1 is sufficient to cause increased expression of inflammatory cytokines and an inflammatory cardiomyopathy leading to heart failure and death.

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Endothelin-1 induces interleukin-6 release via acctivation of the transcription factor NF-κB in human vascular smooth muscle cells

Cited by 145 publications

References 35 publications

Endothelin Antagonism and Interleukin-6 Inhibition Attenuate the Proatherogenic Effects of C-Reactive Protein

Endothelin Antagonism and Interleukin-6 Inhibition Attenuate the Proatherogenic Effects of C-Reactive Protein

Arterial Pressure Response to the Antioxidant Tempol and ET _B Receptor Blockade in Rats on a High-Salt Diet

Conditional Cardiac Overexpression of Endothelin-1 Induces Inflammation and Dilated Cardiomyopathy in Mice

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Endothelin-1 induces interleukin-6 release via acctivation of the transcription factor NF-κB in human vascular smooth muscle cells

Cited by 145 publications

References 35 publications

Endothelin Antagonism and Interleukin-6 Inhibition Attenuate the Proatherogenic Effects of C-Reactive Protein

Endothelin Antagonism and Interleukin-6 Inhibition Attenuate the Proatherogenic Effects of C-Reactive Protein

Arterial Pressure Response to the Antioxidant Tempol and ET B Receptor Blockade in Rats on a High-Salt Diet

Conditional Cardiac Overexpression of Endothelin-1 Induces Inflammation and Dilated Cardiomyopathy in Mice

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Arterial Pressure Response to the Antioxidant Tempol and ET _B Receptor Blockade in Rats on a High-Salt Diet