Cytokines decrease sGC in pulmonary artery smooth muscle cells via NO-dependent and NO-independent mechanisms

Takata, Masao; Filippov, Galina; Liu, Heling; Ichinose, Fumito; Janssens, Stefan; Bloch, Donald B.; Bloch, Kenneth D.

doi:10.1152/ajplung.2001.280.2.l272

Cited by 58 publications

(53 citation statements)

References 20 publications

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“…The potential reduction in concentrations of the guanylate cyclase substrate GTP caused by LPS is not also likely to explain our results, because L-NAME, which inhibits only NOS activity and presumably does not interfere with other LPS effects, restored guanylate cyclase activity. Endogenously produced NO has been implicated in the down-regulation of enzyme mRNA levels that follows the exposure of cultured smooth muscle cells to lipopolysaccharide (Papapetropoulos et al, 1996a;Scott and Nakayama, 1998;Takata et al, 2001). This is in contrast to our in vivo finding that guanylate cyclase mRNA levels are either normal for the ␣1 subunit or increased for the ␤1 subunit 8 h after lipopolysaccharide.…”

Section: Downloaded Fromcontrasting

confidence: 99%

Nitric Oxide-Dependent Reduction in Soluble Guanylate Cyclase Functionality Accounts for Early Lipopolysaccharide-Induced Changes in Vascular Reactivity

Fernandes¹,

Silva-Santos²,

Duma³

et al. 2006

Molecular Pharmacology

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We investigated the role of soluble guanylate cyclase in lipopolysaccharide-induced hyporesponsiveness to phenylephrine. The effects of phenylephrine on the blood pressure of female Wistar rats were evaluated at 2, 8, and 24 h after lipopolysaccharide injection (12.5 mg/kg i.p.). Vasoconstrictive responses to phenylephrine were reduced 40 to 50% in all time periods. Methylene blue, a soluble guanylate cyclase inhibitor (15 mol/kg i.v.) restored the reactivity to phenylephrine in animals injected with lipopolysaccharide 2 and 24 h earlier. However, it failed to do so in animals injected with lipopolysaccharide 8 h earlier. Incubation with sodium nitroprusside (SNP) increased lung and aorta cGMP levels in control animals and in tissues of rats treated with lipopolysaccharide 24 h earlier. However, SNP failed to increase tissue cGMP in rats injected 8 h earlier.Lipopolysaccharide reduced the vasodilatory response to NO donors 8 h after injection. This effect and the decreased lung cGMP accumulation in response to SNP were reversed by an NO synthase blocker. Guanylate cyclase protein levels were lower than controls in lungs harvested from rats injected 8 h earlier and were back to normal values in lungs of rats injected 24 h earlier with lipopolysaccharide. Thus, data indicate that there is a temporal window of 8 h after lipopolysaccharide injection in which soluble guanylate cyclase is not functional and that this loss of function is NO-dependent. Thus, the putative use of soluble guanylate cyclase inhibitors in the treatment of endotoxemia may be beneficial mainly at early stages of this condition.Septic shock, the most severe complication of sepsis, is a serious disorder with significant morbidity and mortality even after the appropriate antibiotic and supportive therapy are initiated. The poor outcome is considered to be a consequence of an overactive systemic inflammatory response elicited by microbial products, mainly lipopolysaccharide. The disease state is characterized by hypotension, hyporeactivity to vasoconstrictor agents, vascular damage and disseminated intravascular coagulation, which leads to multiple organ failure and death (Karima et al., 1999). Because the mortality rate after sepsis is in excess of 50%, it is clear that the present pharmacotherapy is inadequate.Inflammatory stimuli such as lipopolysaccharide activate a pathway that leads to expression, among other proinflammatory proteins, of the inducible nitric-oxide synthase (NOS-2). Once expressed, this enzyme is active for several hours and produces large amounts of nitric oxide (Alderton et al., 2001). It is well established that overproduction of NO in sepsis is one of the main causes of excessive vasodilation and reduced contractile response to vasoconstrictor agents (Titheradge, 1999). Regarding the molecular mechanism of NO-mediated vascular collapse in shock, the role of cGMP-dependent mechanism seems to be well established (Fleming et al., 1991;Paya et al., 1993;Keaney et al., 1994;Silva-Santos et al., 2002). NO activates solu...

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Section: Downloaded Fromcontrasting

confidence: 99%

Nitric Oxide-Dependent Reduction in Soluble Guanylate Cyclase Functionality Accounts for Early Lipopolysaccharide-Induced Changes in Vascular Reactivity

Fernandes¹,

Silva-Santos²,

Duma³

et al. 2006

Molecular Pharmacology

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“…Here, it would be appropriate for sGC expression to be down-regulated to offset the excessive NO levels and thereby reverse the associated, life-threatening hypotension. These data also suggest that the reduction in sGC mRNA levels reported in vascular smooth muscle cells in response to LPS/interleukin-1␤ (27), tumor necrosis factor-␣/ LPS (53), and NO donors (54,55) is likely to be due, at least in part, to a direct down-regulation in sGC promoter activity via NF-B(p50)-and CCAAT-BF-dependent pathways.…”

Section: Discussionmentioning

confidence: 65%

Characterization of the Human α1β1 Soluble Guanylyl Cyclase Promoter

Marro

Peiró

Panayiotou

et al. 2008

Journal of Biological Chemistry

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Soluble guanylyl cyclase (sGC) is the principal receptor for NO and plays a ubiquitous role in regulating cellular function. This is exemplified in the cardiovascular system where sGC governs smooth muscle tone and growth, vascular permeability, leukocyte flux, and platelet aggregation. As a consequence, aberrant NO-sGC signaling has been linked to diseases including hypertension, atherosclerosis, and stroke. Despite these key (patho)physiological roles, little is known about the expressional regulation of sGC. To address this deficit, we have characterized the promoter activity of human ␣ 1 and ␤ 1 sGC genes in a cell type relevant to cardiovascular (patho)physiology, primary human aortic smooth muscle cells. Luciferase reporter constructs revealed that the 0.3-and 0.5-kb regions upstream of the transcription start sites were optimal for ␣ 1 and ␤ 1 sGC promoter activity, respectively. Deletion of consensus sites for c-Myb, GAGA, NFAT, NF-B(p50), and CCAAT-binding factor(s) (CCAAT-BF) revealed that these are the principal transcription factors regulating basal sGC expression. In addition, under pro-inflammatory conditions, the effects of the strongest ␣ 1 and ␤ 1 sGC repressors were enhanced, and enzyme expression and activity were reduced; in particular, NF-B(p50) is pivotal in regulating enzyme expression under such conditions. NO itself also elicited a cGMP-independent negative feedback effect on sGC promoter activity that is mediated, in part, via CCAAT-BF activity. In sum, these data provide a systematic characterization of the promoter activity of human sGC ␣ 1 and ␤ 1 subunits and identify key transcription factors that govern subunit expression under basal and pro-inflammatory (i.e. atherogenic) conditions and in the presence of ligand NO.

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“…Treatment of cultured cells with inflammatory stimuli attenuates the sGC mRNA stability or protein expression (17)(18)(19)(20). Increased inflammation and TNF-α, IL-6 or IL-1β upregulation was documented in the BALF of mice after RB.…”

Section: Inhibition Of Sgc Activity By Odq Worsens Rb-induced Lung Inmentioning

confidence: 98%

Guanylyl Cyclase Activation Reverses Resistive Breathing–Induced Lung Injury and Inflammation

Glynos

Toumpanakis

Loverdos

et al. 2015

Am J Respir Cell Mol Biol

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Cytokines decrease sGC in pulmonary artery smooth muscle cells via NO-dependent and NO-independent mechanisms

Cited by 58 publications

References 20 publications

Nitric Oxide-Dependent Reduction in Soluble Guanylate Cyclase Functionality Accounts for Early Lipopolysaccharide-Induced Changes in Vascular Reactivity

Nitric Oxide-Dependent Reduction in Soluble Guanylate Cyclase Functionality Accounts for Early Lipopolysaccharide-Induced Changes in Vascular Reactivity

Characterization of the Human α1β1 Soluble Guanylyl Cyclase Promoter

Guanylyl Cyclase Activation Reverses Resistive Breathing–Induced Lung Injury and Inflammation

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