Interleukin-1 beta and tumor necrosis factor-alpha synergistically induce NO synthase in rat vascular smooth muscle cells

Beasley, Donald E.; Eldridge, Marlowe W.

doi:10.1152/ajpregu.1994.266.4.r1197

Cited by 53 publications

(53 citation statements)

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“…The fold-increase in iNOS mRNA expression was difficult to quantify because non-treated cells express little if any measurable iNOS. Nevertheless, these findings confirmed those of other laboratories and demonstrated that the cytokine signaling pathway that is responsible for iNOS expression was present in both the primary and the passaged VSMC (25,26).…”

Section: Resultssupporting

confidence: 91%

Regulation of cGMP-dependent Protein Kinase Expression by Soluble Guanylyl Cyclase in Vascular Smooth Muscle Cells

Browner

Dey

Bloch

et al. 2004

Journal of Biological Chemistry

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Vascular smooth muscle cells (VSMC) undergo many phenotypic changes when placed in culture. Several studies have shown that the levels of expression of soluble guanylyl cyclase (sGC) or cGMP-dependent protein kinase (PKG) are altered in cultured VSMC. In this study the mechanisms involved in the coordinated expression of sGC and PKG were examined. Pro-inflammatory cytokines that increase the expression of type II NO synthase (inducible NO synthase, or iNOS) decreased PKG expression in freshly isolated, non-passaged bovine aortic SMC. However, in several passaged VSMC lines (i.e. bovine aortic SMC, human aortic SMC, and A7r5 cells), PKG protein expression was not suppressed by cytokines or NO. sGC was highly expressed in nonpassaged bovine aortic SMC but not in passaged cell lines. Restoration of expression of sGC to passaged bovine SMC using adenovirus encoding the ␣ 1 and ␤ 1 subunits of sGC restored the capacity of the cells to increase cGMP in response to NO. Furthermore, treatment of these sGC-transduced cells with NO donors for 48 h resulted in decreased PKG protein expression. In contrast, passaged rat aortic SMC expressed high levels of NOresponsive sGC but demonstrated reduced expression of PKG. Adenovirus-mediated expression of the PKG catalytically active domain in rat aortic SMC caused a reduction in the expression of sGC in these cells. These results suggest that there is a mechanism for the coordinated expression of sGC and PKG in VSMC and that prolonged activation of sGC down-regulates PKG expression. Likewise, the loss of PKG expression appears to increase sGC expression. These effects may be an adaptive mechanism allowing growth and survival of VSMC in vitro.The nitric oxide (NO)-cGMP signaling pathway plays a critical role in vascular function (1, 2). Cyclic GMP is a second messenger that is generated by cytoplasmic soluble guanylyl cyclases (sGCs), 1 which are activated by NO, or particulate guanylyl cyclases, which are activated by peptide hormones such as atrial natriuretic peptide. sGC is a heterodimer that consists of two subunits, termed ␣ and ␤, which are linked by disulfide bonds, and has a prosthetic heme group covalently bound to the heterodimer (1, 2). NO activates cGMP synthesis by binding to the heme, leading to the conversion of GTP to cGMP. Although two isoforms of each subunit have been cloned from rat and bovine lung, the a 1 b 1 heterodimer has been found in most tissues and cell types, including vascular smooth muscle cells (VSMC) (3-6). NO and cGMP are involved in many physiological processes such as VSMC relaxation, apoptosis, proliferation, migration, and extracellular matrix production (7-10). An important cGMP receptor protein expressed in VSMC is cGMP-dependent protein kinase (PKG), which is ultimately responsible for mediating the effects of cGMP in vascular smooth muscle relaxation (11). There are two distinct genes encoding PKG in mammalian cells, the type I and type II genes (12, 13). Type I, which is the gene product expressed in VSMC, exists as two isoforms, PKG I␣...

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Section: Resultssupporting

confidence: 91%

Regulation of cGMP-dependent Protein Kinase Expression by Soluble Guanylyl Cyclase in Vascular Smooth Muscle Cells

Browner

Dey

Bloch

et al. 2004

Journal of Biological Chemistry

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“…31,32 Among several inflammatory cytokines, IL-1␤ is considered one of the most potent stimuli for iNOS induction in SMCs. [33][34][35] Accordingly, in this study, we investigated the regulatory mechanisms of NOx production by iNOS in IL-1␤-stimulated cultured SMCs. In the control state, without IL-1␤ stimulation, ADMA accumulated time dependently in the culture media, which may have been attributable to spontaneous degradation of methylated protein, a source of ADMA.…”

Section: Inos and Ddah Expression In Smcsmentioning

confidence: 99%

Regulation of Cytokine-Induced Nitric Oxide Synthesis by Asymmetric Dimethylarginine

Ueda

Kato

Matsuoka

et al. 2003

Circulation Research

138

115

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Abstract-In response to vascular insults, inflammatory cytokines stimulate vascular smooth muscle cells (SMCs) to express an inducible isoform of nitric oxide synthase (iNOS). Asymmetric dimethylarginine (ADMA), an endogenous NO synthase inhibitor, is metabolized by dimethylarginine dimethylaminohydrolase (DDAH). To determine whether the ADMA-DDAH system regulates cytokine-induced NO production, cultured rat SMCs were exposed to interleukin-1␤ (IL-1␤). IL-1␤ (1 to 100 U/mL) dose-dependently stimulated not only iNOS but also DDAH expression and enzyme activity, accompanied by an increase in NO metabolite and by a decrease in ADMA content in culture media. A DDAH inhibitor (4124W, 5 mmol/L) augmented ADMA production (PϽ0.01) and decreased NO synthesis (PϽ0.01) in IL-1␤-stimulated SMCs. On the other hand, an adenovirus-mediated overexpression of DDAH reduced ADMA and enhanced NO production. Exogenous administration of NO donors (SNAP and SIN-1) dose-dependently increased NO metabolite in the culture media but had no effect on ADMA. Our results indicate two mechanisms of IL-1␤-induced NO synthesis: the direct stimulation of the expression of iNOS and the indirect stimulation of iNOS activity by upregulating DDAH and reducing ADMA. The ADMA-DDAH system may be another regulatory mechanism of inflammation-mediated NO production for human vascular diseases. Key Words: nitric oxide Ⅲ nitric oxide synthase Ⅲ interleukins Ⅲ smooth muscle Ⅲ atherosclerosis N itric oxide (NO) plays an important role in the regulation of not only vascular tone but also architecture. There are two types of nitric oxide synthase in vessels, endotheliumderived NO synthase (eNOS) and inducible NO synthase (iNOS); the former is constitutively present in the endothelium, and the latter is induced by the inflammatory stimuli in the vascular wall. 1,2 N G ,N G Ϫ Dimethyl-L-arginine (ADMA) is an endogenous NOS inhibitor that inhibits activities of both eNOS and iNOS. We and others have demonstrated that increased plasma levels of ADMA are associated with hypertension, 3 hypercholesterolemia, 4 and the clustering of coronary risk factors in vivo in humans. 5 Furthermore, a close association has been found between plasma ADMA level and carotid intima-media thickness 5 or the severity of peripheral arterial occlusive diseases. 6 These lines of evidence suggest that ADMA is involved in the pathophysiology of human vascular diseases. ADMA is metabolized by a key limiting enzyme, N G ,N G Ϫ dimethylarginine dimethylaminohydrolase (DDAH). 7-9 DDAH is identified in human aortic tissues. 10 -13 It has been reported that oxidized low-density lipoprotein upregulates the synthesis of ADMA in cultured human endothelial cells in association with decreased activity of DDAH. 13 Collectively, the ADMA-DDAH system may be involved in the regulation of endogenous NO synthesis. 14 -17 Inflammatory response plays a crucial role in human vascular diseases. 18 Monocyte-derived macrophages, recognized at every stage of disease, promote continuous activation of the cytokine ...

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“…Upon release into the systemic circulation, LPS binds to plasma proteins and lipids activating macrophages to secrete proinflammatory cytokines such as tumor necrosis factor ␣ (TNF ␣ ) and IL-1, IL-6, and IL-8 (3). Recently, the ability of cytokines and LPS to stimulate the synthesis of nitric oxide (NO) 1 by activation of NO-synthase (NOS) in macrophages, neutrophils, endothelial and vascular smooth muscle cells has generated substantial interest (4)(5)(6)(7). Three isoforms of NOS have been cloned, sequenced, and expressed, two of which are regulated by intracellular calcium and expressed constitutively in endothelial (cNOS, NOS3) and neuronal cells (bNOS, NOS1), respectively (8).…”

Section: Introductionmentioning

confidence: 99%

Polymerized hemoglobin restores cardiovascular and kidney function in endotoxin-induced shock in the rat.

Heneka

Löschmann²,

Oßwald³

1997

J. Clin. Invest.

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Interleukin-1 beta and tumor necrosis factor-alpha synergistically induce NO synthase in rat vascular smooth muscle cells

Cited by 53 publications

References 0 publications

Regulation of cGMP-dependent Protein Kinase Expression by Soluble Guanylyl Cyclase in Vascular Smooth Muscle Cells

Regulation of cGMP-dependent Protein Kinase Expression by Soluble Guanylyl Cyclase in Vascular Smooth Muscle Cells

Regulation of Cytokine-Induced Nitric Oxide Synthesis by Asymmetric Dimethylarginine

Polymerized hemoglobin restores cardiovascular and kidney function in endotoxin-induced shock in the rat.

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